IL-6 in inflammation, autoimmunity and cancer

In the paper

“Consistently, evidence has indicated that interactions between immune cells and non-immune tissues play critical roles in chronic inflammatory diseases and autoimmune diseases (3, 41, 49–51).”

What the sources say

• ?Not checked — no full text of the sourcecites [3] Ishihara, 2002, IL-6 in autoimmune disease and chronic inflammatory proliferative disease, Cytokine Growth Factor Rev. source
• Partly supported

  In “The view from the mountaintop,” the paper says its model implies that interactions between nonimmune and immune systems may play critical roles in autoimmune diseases and chronic inflammatory proliferative disease. The citing sentence presents that tentative, model-based conclusion as an established role across chronic inflammatory diseases more broadly. (LLM, conf=0.84)

  cites [41] Hirano, 2010, Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir, Proc. Jpn Acad. Ser. B. Phys. Biol. Sci. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [49] Matsumoto, 2002, How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease, Nat. Immunol. source
• ?Not checked — no full text of the sourcecites [50] Marrack, 2001, Autoimmune disease: why and where it occurs, Nat. Med. source
• ?Not checked — no full text of the sourcecites [51] Hirano, 2002, Revival of the autoantibody model in rheumatoid arthritis, Nat. Immunol. source

In the paper

“Furthermore, tissue property-dependent events (49), microbleeding (52, 53), neural stimulation (54, 55), cell senescence (56, 57) and oncogenic mutations in pre-neoplastic cells have been shown to trigger these interactions.”

What the sources say

• ?Not checked — no full text of the sourcecites [49] Matsumoto, 2002, How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease, Nat. Immunol. source
• Supported

  This citation is attached to microbleeding, not to the other events listed in the sentence. The Discussion describes microbleeding as a local event that induces tissue-specific accumulation of activated T cells, which can then enhance IL-6 signaling in the affected tissue. (LLM, conf=0.90)

  cites [52] Murakami, 2011, Local microbleeding facilitates IL-6- and IL-17-dependent arthritis in the absence of tissue antigen recognition by activated T cells, J. Exp. Med. source
• ?Not checked — no full text of the sourcecites [53] Leavy, 2011, Autoimmunity: joint damage without antigen, Nat. Rev. Immunol. source

In the paper

“Additionally, interactions between a tumor and its microenvironment through the immune system are critical for tumor development and progression (2, 6, 9, 58–60)”

What the sources say

• ?Not checked — no full text of the sourcecites [2] Balkwill, 2001, Inflammation and cancer: back to Virchow?, Lancet source
• Supported

  The opening section (p. 1) says inflammation in the tumour microenvironment promotes tumour development, survival, angiogenesis and metastasis. The adaptive-immunity section (p. 5) and Figure 4 (p. 6) describe immune cells and signalling within that environment affecting tumour development and progression. (LLM, conf=0.93)

  cites [6] Mantovani, 2008, Cancer-related inflammation, Nature source
• Supported

  The “Immune cells in tumorigenesis” section says that immune cells and cancer cells in the tumor microenvironment communicate to control and shape tumor growth. It also explains that immune mediators can either inhibit tumor development or enhance progression, supporting the claim without implying that every immune interaction promotes cancer. (LLM, conf=0.93)

  cites [9] Grivennikov, 2010, Immunity, inflammation, and cancer, Cell source

In the paper

“It too plays a key role in inflammatory diseases including cytokine storm syndromes, autoimmune diseases and cancer (10, 11, 15, 41, 66–68)”

What the sources say

• Partly supported

  The Discussion (page not specified) describes the IL-6 amplifier as important in chronic inflammation and reports associations with autoimmune diseases, including rheumatoid arthritis and lupus. The passages found do not support the added claims about cytokine storm syndromes or cancer. (LLM, conf=0.88)

  cites [10] Murakami, 2013, Disease-association analysis of an inflammation-related feedback loop, Cell Rep. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [11] Atsumi, 2014, Inflammation amplifier, a new paradigm in cancer biology, Cancer Res. source
• Partly supported

  The Main Text says the IL-6 amplifier can lead to inflammatory and autoimmune diseases. It also proposes a possible role in cytokine release syndrome, rather than establishing a key role. Cancer is mentioned as the condition treated by CAR-T cells, not as a disease in which the IL-6 amplifier plays a key role. (LLM, conf=0.87)

  cites [15] Hirano, 2020, COVID-19: a new virus, but a familiar receptor and cytokine release syndrome, Immunity sourceExperimental — accuracy not yet measured

In the paper

“The IL-6–STAT3 pathway is now considered a major target for the treatment of inflammatory diseases (15, 19, 21, 24–26, 76).”

What the sources say

• Partly supported

  The Main Text (page unavailable) identifies the IL-6–STAT3 axis as a potential target for cytokine release syndrome in later-stage COVID-19 and links IL-6–STAT3 signaling to inflammatory and autoimmune diseases. It does not establish the pathway as a major treatment target for inflammatory diseases generally; that broader, more definite claim exceeds the paper's qualified proposal. (LLM, conf=0.86)

  cites [15] Hirano, 2020, COVID-19: a new virus, but a familiar receptor and cytokine release syndrome, Immunity sourceExperimental — accuracy not yet measured
• Partly supported

  In “Targeting STAT3 for cancer therapy” (page not supplied), the paper calls JAK kinases in IL-6–STAT3 signalling crucial targets for inflammation-induced cancer and cancer-associated inflammation. That supports targeting the pathway in a cancer-related setting, but not the broader claim that it is a major treatment target for inflammatory diseases generally. (LLM, conf=0.86)

  cites [19] Yu, 2009, STATs in cancer inflammation and immunity: a leading role for STAT3, Nat. Rev. Cancer sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [21] Hunter, 2015, IL-6 as a keystone cytokine in health and disease, Nat. Immunol. source

In the paper

“However, this site is also a recruitment motif for SOCS3, and it was found that the F759/F757-dependent negative regulation is mainly dependent on the recruitment of SOCS3 (116, 117).”

What the sources say

• Partly supported

  The opening summary and Results report that SOCS3 acts through gp130 Tyr-759 and that its inhibitory activity depends on that site. But the paper also finds an independent inhibitory role for SHP2 and describes two largely distinct modes of negative regulation; it does not establish that SOCS3 recruitment accounts for most of the site-dependent effect. Our copy addresses Tyr-759, not the cited F757 counterpart. (LLM, conf=0.84)

  cites [116] Lehmann, 2003, SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• Supported

  The Introduction reports that a gp130 receptor mutant with reduced SOCS3 recruitment but retained SHP2 binding showed elevated cytokine responsiveness, like a Y757F mutant. The Discussion identifies Y757 as the shared docking site. Together, these passages support the claim that Y757-dependent negative regulation depends mainly on SOCS3 recruitment; the paper does not separately test F759. (LLM, conf=0.90)

  cites [117] Fairlie, 2003, Negative regulation of gp130 signalling mediated through tyrosine-757 is not dependent on the recruitment of SHP2, Biochem. J. source

In the paper

“Indeed, this mode plays crucial roles in chronic inflammation (33, 96).”

What the sources say

• ?Could not verify

  The supplied passage has no section or page label and consists of reference links, not discussion of trans-signaling. Searches of our copy for “trans-signaling,” “chronic inflammation,” and related IL-6 signaling terms found no substantive passage addressing the claim. (LLM, conf=0.72)

  cites [33] Murakami, 2019, Pleiotropy and specificity: insights from the interleukin 6 family of cytokines, Immunity sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [96] Rose-John, 2017, The soluble interleukin 6 receptor: advanced therapeutic options in inflammation, Clin. Pharmacol. Ther. source

In the paper

“STAT3-induced microRNA (miR)-21 and miR-181b-1 activate NF-κB, resulting in the induction of IL-6 gene expression (90).”

What the sources say

• Supported

  The Results section reports that STAT3 activates miR-21 and miR-181b-1. Its CYLD subsection links miR-181b-1 to increased NF-κB activity and IL6 production; its PTEN/Akt subsection links miR-21 to NF-κB activation and reports that Akt inhibition reduces IL6 production. Page numbers are not provided in our copy. (LLM, conf=0.91)

  cites [90] Iliopoulos, 2010, STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer, Mol. Cell source

In the paper

“The IL-6R is composed of an IL-6-binding receptor molecule (IL-6Rα) and a signal transducer, gp130, which is shared among the IL-6 family of cytokines (Fig. 1A) (33).”

What the sources say

• ?Could not verify

  The passages from our copy contain reference links and corrupted section headings, but no readable discussion of IL-6R composition. Searches for IL-6Rα, gp130, and shared IL-6-family receptor subunits returned no passage that addresses the claim. (LLM, conf=0.72)

  cites [33] Murakami, 2019, Pleiotropy and specificity: insights from the interleukin 6 family of cytokines, Immunity sourceExperimental — accuracy not yet measured

In the paper

“Similarly, defective STAT3 activation enhances SHP-2–ERK–MAPK activation pathways, most likely through an impaired STAT3-mediated induction of suppressor of cytokine signaling 3 (SOCS3) (111, 112).”

What the sources say

• Partly supported

  The Results section, “Sustained Activation of the SHP-2/ras/Erk Pathway Results from Impaired Induction of SOCS-1” (page unavailable), links impaired STAT signaling to sustained SHP-2/ras/Erk activation and reports reduced SOCS-3 induction. It does not establish the specific STAT3-to-SOCS3 mechanism claimed: it emphasizes SOCS-1 and describes induction of both SOCS-1 and SOCS-3 as mediated at least in part by STATs. (LLM, conf=0.86)

  cites [111] Ernst, 2001, Defective gp130-mediated signal transducer and activator of transcription (STAT) signaling results in degenerative joint disease, gastrointestinal ulceration, and failure of uterine implantation, J. Exp. Med. sourceExperimental — accuracy not yet measured
• Supported

  The Discussion reports that loss of gp130-dependent STAT1/3 signaling increases IL-6-induced SHP2 and ERK1/2 phosphorylation because STAT-mediated induction of SOCS1 and SOCS3 is impaired. The Results also show enhanced ERK1/2 phosphorylation after IL-6 stimulation in macrophages with defective gp130-dependent STAT signaling. The claim captures this mechanism, although the paper names SOCS1 alongside SOCS3. (LLM, conf=0.90)

  cites [112] Jenkins, 2004, Imbalanced gp130-dependent signaling in macrophages alters macrophage colony-stimulating factor responsiveness via regulation of c-fms expression, Mol. Cell. Biol. source

In the paper

“The IL-6–STAT3–Pim kinase axis is involved in the development and cell growth of pancreatic cancer (128, 129).”

What the sources say

• Partly supported

  The Introduction and Discussion (page unavailable) support a role for IL-6–STAT3 signaling in pancreatic cancer and report that IL-6 increases Pim-1 expression. But the Discussion reports no increased proliferation after IL-6 stimulation, and the Results found no significant growth difference with Pim-1 overexpression. The paper therefore does not establish that the full axis promotes pancreatic cancer cell growth; it describes Pim-1’s effects as context dependent. (LLM, conf=0.88)

  cites [128] Block, 2012, IL-6 stimulates STAT3 and Pim-1 kinase in pancreatic cancer cell lines, Pancreas sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion says PIM kinases contribute to pancreatic cancer development and progression, and reports that PIM-1 knockdown inhibited cancer-cell proliferation. It also lists increased phosphorylated STAT3 as a possible effect of PIM-3. Neither the Discussion nor a search for IL-6 supports the specific IL-6–STAT3–Pim kinase axis claimed. (LLM, conf=0.86)

  cites [129] Xu, 2016, PIM-1 contributes to the malignancy of pancreatic cancer and displays diagnostic and prognostic value, J. Exp. Clin. Cancer Res. sourceExperimental — accuracy not yet measured

In the paper

“These multiple signal transduction pathways intimately regulate cell survival, proliferation, inflammation, immunity, angiogenesis, and tumor development and progression through the expression of several genes (1, 19, 21, 26, 31).”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Hirano, 1998, Interleukin 6 and its receptor: ten years later, Int. Rev. Immunol. source
• Supported

  The passage labelled Abstract describes STAT3 and NF-κB as signalling pathways that regulate genes involved in tumour proliferation, survival, angiogenesis and inflammatory mediators. The passages on anti-cancer and pro-cancer inflammation and on STAT3-induced inflammation also connect STAT signalling to immunity and tumour progression. Our copy provides section labels but no page numbers. (LLM, conf=0.90)

  cites [19] Yu, 2009, STATs in cancer inflammation and immunity: a leading role for STAT3, Nat. Rev. Cancer source
• ?Not checked — no full text of the sourcecites [21] Hunter, 2015, IL-6 as a keystone cytokine in health and disease, Nat. Immunol. source

In the paper

“STAT3 activation by IL-6 is required for intestinal epithelial cell survival and cell-cycle progression during colitis-induced tumorigenesis (20).”

What the sources say

• Partly supported

  The Summary (page unavailable) reports that Stat3 mediates IL-6- and IL-11-dependent intestinal epithelial cell survival and promotes cell-cycle progression in a colitis-associated cancer model. But the section “Stat3 Stimulates Regeneration and Proliferation during Colitis” (page unavailable) reports that loss of IL-6 signaling alone did not reduce epithelial proliferation; IL-6 and IL-11 had redundant activity. The paper therefore supports a role for Stat3, but not a requirement for IL-6 specifically. (LLM, conf=0.87)

  cites [20] Bollrath, 2009, gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis, Cancer Cell sourceExperimental — accuracy not yet measured

In the paper

“IL-6-induced STAT3 activation is critical for in vivo plasma cell survival and immunoglobulin secretion in humans (154).”

What the sources say

• Supported

  The Discussion (page unavailable) states that IL-6 activates STAT3 in human blood and bone-marrow plasma cells and that blocking this pathway blocks IL-6’s effects. It also reports that IL-6 supports survival and IgG secretion in blood plasma cells; the effects differ by cell source, with bone-marrow plasma cells requiring IL-6 for sustained secretion but not increased viability. (LLM, conf=0.90)

  cites [154] Rodríguez-Bayona, 2013, STAT-3 activation by differential cytokines is critical for human in vivo-generated plasma cell survival and Ig secretion, J. Immunol. source

In the paper

“and serum IL-6 levels in RA patients correlate with clinical and laboratory indices of the disease (234).”

What the sources say

• Partly supported

  The Abstract reports a significant correlation between serum IL-6 and C-reactive protein, a laboratory index. It does not report a significant correlation between IL-6 and a clinical index: the other association named is between the Ritchie articular index and morning stiffness, and it says no other correlations were observed. (LLM, conf=0.86)

  cites [234] Madhok, 1993, Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity, Ann. Rheum. Dis. sourceExperimental — accuracy not yet measured

In the paper

“On the other hand, the enhancement of IL-6–STAT3 signaling causes IL-17A-dependent autoimmune arthritis in mice (41, 63, 66).”

What the sources say

• Supported

  In “The view from the mountaintop,” the paper reports that F759 mice have enhanced IL-6–STAT3 signaling and spontaneously develop autoimmune, RA-like arthritis. The same section states that F759 arthritis depends on IL-17A. (LLM, conf=0.92)

  cites [41] Hirano, 2010, Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir, Proc. Jpn Acad. Ser. B. Phys. Biol. Sci. source
• Partly supported

  The Introduction reports that gp130 mutant mice have enhanced STAT3 signaling and spontaneously develop lymphocyte-dependent arthritis; the Discussion links augmented gp130-mediated STAT3 activation to autoimmune joint disease. The paper does not establish that the arthritis is IL-17A-dependent: its Discussion identifies a requirement for lymphocytes, not IL-17A (searched: IL-17A, interleukin 17, Th17). (LLM, conf=0.89)

  cites [63] Atsumi, 2002, A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis, J. Exp. Med. sourceExperimental — accuracy not yet measured
• Supported

  The Discussion reports that enhanced signaling through the IL-17A-triggered IL-6 feedback loop plays a central role in arthritis in F759 mice. It also reports that deleting STAT3 in fibroblasts suppressed arthritis, and that F759 mice lacking IL-17A had significantly reduced arthritis scores. The claim is supported for this mouse model. (LLM, conf=0.91)

  cites [66] Ogura, 2008, Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction, Immunity source

In the paper

“MDSC function is dependent on STAT3 (25).”

What the sources say

• Supported

  Section 3.3 identifies STAT3 as a major regulator of MDSC function. It reports that turning off STAT3 in patient-derived myeloid cells abrogated MDSCs’ immunosuppressive effects on effector CD8+ T cells, supporting the claim about suppressive function. (LLM, conf=0.92)

  cites [25] Rebe, 2019, STAT3, a master regulator of anti-tumor immune response, Cancer source

In the paper

“Chronic inflammation is often accompanied with autoimmune disease and cancer (2, 4, 9).”

What the sources say

• ?Not checked — no full text of the sourcecites [2] Balkwill, 2001, Inflammation and cancer: back to Virchow?, Lancet source
• Supported

  The section “Cancers associated with chronic inflammation” links chronic inflammation to malignancy, particularly colorectal cancer in people with inflammatory bowel disease. Its table of chronic inflammatory conditions associated with neoplasms also lists Sjögren syndrome and Hashimoto’s thyroiditis, supporting the autoimmune-disease part of this broad background claim. Our copy provides no page number for these passages. (LLM, conf=0.85)

  cites [4] Coussens, 2002, Inflammation and cancer, Nature source
• Supported

  The ‘Types of inflammation and general mechanisms’ section (page unavailable) describes autoimmunity as a cause of chronic inflammation and gives inflammatory bowel disease as an example that increases colorectal cancer risk. The paper also says chronic inflammation increases cancer risk, while noting that not every chronic inflammatory disease does so; the claim’s ‘often’ allows for that qualification. (LLM, conf=0.86)

  cites [9] Grivennikov, 2010, Immunity, inflammation, and cancer, Cell source

In the paper

“Therefore, rather than the dogma that oncogenesis is intrinsically triggered in pre-neoplastic cells, environmental factors, such as infection, stress, obesity, aging and smoking, each of which can induce chronic inflammation, could be a major cause of oncogenesis (4, 6, 9, 233).”

What the sources say

• Partly supported

  The passage headed “Cancers associated with chronic inflammation” (indexed as Abstract; page unavailable) says persistent infections induce chronic inflammation and that many malignancies arise from sites of infection and inflammation. Table 1 (indexed as Abstract; page unavailable) also lists smoking as an aetiologic agent for bronchitis associated with lung carcinoma. The copy does not establish the same pathway for stress, obesity or aging, or that these factors collectively are a major cause of oncogenesis. (LLM, conf=0.87)

  cites [4] Coussens, 2002, Inflammation and cancer, Nature sourceExperimental — accuracy not yet measured
• Partly supported

  The ‘Cancer-related inflammation’ section (p. 1) says chronic inflammation predisposes people to cancer and identifies microbial infection as one trigger. ‘Connecting inflammation and oncogenes’ (pp. 1–2) describes an extrinsic inflammatory pathway alongside an intrinsic genetic pathway. Our copy does not establish that stress, obesity, aging and smoking each induce chronic inflammation and cause oncogenesis; ‘The big questions’ (p. 7) also says formal proof that inflammation itself causes cancer is still required. (LLM, conf=0.88)

  cites [6] Mantovani, 2008, Cancer-related inflammation, Nature sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction links infection, smoking, obesity, and older age to cancer risk or tumor promotion through inflammatory mechanisms; Conclusions and Prospective says inflammation can affect tumorigenesis from initiation onward. Our copy does not support stress as another such environmental factor, and it also describes intrinsic tumor-triggered inflammation rather than ruling it out. (LLM, conf=0.86)

  cites [9] Grivennikov, 2010, Immunity, inflammation, and cancer, Cell sourceExperimental — accuracy not yet measured

In the paper

“Gp130Y757F/Y757F mice show enhanced colitis-associated tumorigenesis in a manner dependent on the enhanced activation of STAT3 (20).”

What the sources say

• Supported

  In “Intestinal Stat3 Activity Modulates Colitis-Associated Tumorigenesis” (Figure 1), gp130 Y757F mice had more frequent and larger AOM+DSS-induced tumors than wild-type mice. The authors describe this as a Stat3 gain-of-function model and conclude that epithelial Stat3 activation has a dose-response relationship with tumor incidence and growth. (LLM, conf=0.92)

  cites [20] Bollrath, 2009, gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis, Cancer Cell source

In the paper

“However, true pathogenic antigens causing the breakdown have not been identified for many autoimmune diseases, including RA and other tissue-specific disorders (229–231).”

What the sources say

• ?Could not verify

  The Pleiotropy section discusses genetic variants associated with rheumatoid arthritis, while Unchartered regions discusses unidentified candidate genes in type 1 diabetes. Neither addresses whether pathogenic antigens responsible for a breakdown of tolerance have been identified in rheumatoid arthritis or other tissue-specific disorders (searched: pathogenic antigens, autoantigens, breakdown of tolerance). (LLM, conf=0.74)

  cites [229] Inshaw, 2018, Approaches and advances in the genetic causes of autoimmune disease and their implications, Nat. Immunol. sourceExperimental — accuracy not yet measured
• ?Could not verify

  The gut microbiome and dietary factors section mentions rheumatoid arthritis only in connection with the gut microbiome. The mechanisms of disease pathogenesis section discusses immune cells in multiple sclerosis, but neither section says that pathogenic antigens remain unidentified in rheumatoid arthritis or other tissue-specific autoimmune diseases. Searches for unidentified pathogenic antigens and autoantigens found no passage addressing that claim; page numbers were not available in our copy. (LLM, conf=0.72)

  cites [230] Rothhammer, 2016, Environmental control of autoimmune inflammation in the central nervous system, Curr. Opin. Immunol. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [231] Mathis, 2004, Back to central tolerance, Immunity source

In the paper

“In line with these findings, several inflammatory and autoimmune diseases, including RA, MS and inflammatory bowel disease show a bias for Th17 cells over Treg cells (163).”

What the sources say

• Supported

  The Conclusions state that Th17 dominance or dysfunctional Treg surveillance is associated with MS, RA and IBD. The “Th17/Treg in Autoimmunity” section also identifies an altered balance between these cells in all three diseases. (LLM, conf=0.93)

  cites [163] Knochelmann, 2018, When worlds collide: Th17 and Treg cells in cancer and autoimmunity, Cell. Mol. Immunol. source

In the paper

“For example, STAT3 prolongs NF-κB nuclear retention through acetyltransferase p300-mediated RelA acetylation, thereby interfering with NF-κB nuclear export in both cancer cells and tumor-associated hematopoietic cells (277).”

What the sources say

• Supported

  The Results report that Stat3 and p300 increase RelA acetylation and that Stat3-mediated nuclear retention requires RelA acetylation. They also report Stat3-dependent RelA acetylation in tumor-associated myeloid cells. The paper’s Abstract explicitly connects this mechanism to impaired NF-κB nuclear export in both cancer cells and tumor-associated hematopoietic cells. Page numbers are not provided in our copy. (LLM, conf=0.94)

  cites [277] Lee, 2009, Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors, Cancer Cell source

In the paper

“In fact, a mutated gp130-mediated excessive production of cytokines and chemokines in non-immune cells in F759 mice is necessary for CD4(+) T-cell proliferation, Th17 cell accumulation in the lesion and the arthritis development (66, 99).”

What the sources say

• Partly supported

  The Introduction (page unavailable) says the F759 mutation in nonhematopoietic cells is essential for CD4+ T-cell homeostatic proliferation and arthritis development. The paper also reports increased IL-6 and the chemokine KC in F759 fibroblasts, and more Th17 cells in older F759 mice, but it does not establish that this production is necessary for Th17 accumulation in the lesion. (LLM, conf=0.88)

  cites [66] Ogura, 2008, Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction, Immunity sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (page not provided) show that the gp130 mutation in nonhematopoietic cells is necessary for arthritis in F759 mice, and report enhanced IL-7 expression in those cells; the paper also links CD4+ T-cell homeostatic proliferation to disease. Our copy does not establish that excessive production of cytokines and chemokines in non-immune cells is necessary for all these outcomes, and it does not report Th17-cell accumulation in lesions. (LLM, conf=0.88)

  cites [99] Sawa, 2006, Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4+ T cells, J. Exp. Med. sourceExperimental — accuracy not yet measured

In the paper

“LOF mutations of TRAF3, a negative regulator of IL-6–STAT3 signaling, are observed in B-cell lymphoma and multiple myeloma patients (122, 273, 274).”

What the sources say

• Supported

  The Introduction reports loss-of-function TRAF3 mutations in B-cell lymphoma patients and in multiple myeloma cell lines and patient tumor samples. The Results section reports that TRAF3 inhibits IL-6–stimulated STAT3 activation in B cells. (LLM, conf=0.94)

  cites [122] Lin, 2015, The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development, Sci. Signal. source
• ?Not checked — no full text of the sourcecites [273] Annunziata, 2007, Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma, Cancer Cell source
• ?Not checked — no full text of the sourcecites [274] Keats, 2007, Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma, Cancer Cell source

In the paper

“Therefore, there is an in vivo positive-feedback amplification loop of IL-6 production via Th17 cell differentiation and their interaction with non-immune cells, such as fibroblasts (41).”

What the sources say

• Supported

  In “The view from the mountaintop” (page not specified), the paper says IL-6 induces Th17 cells to produce IL-17A, which induces IL-6 expression in nonimmune cells such as fibroblasts, completing a positive-feedback loop. It also reports that this IL-6 amplifier is required for F759 autoimmune arthritis in nonimmune tissues, supporting the in vivo aspect. (LLM, conf=0.94)

  cites [41] Hirano, 2010, Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir, Proc. Jpn Acad. Ser. B. Phys. Biol. Sci. source

In the paper

“Somatic GOF mutations in gp130 that activate gp130–STAT3 signaling lead to inflammatory hepatocellular tumors (272).”

What the sources say

• Supported

  The Abstract identifies somatic gain-of-function mutations in gp130 in inflammatory hepatocellular adenomas and reports that gp130 mutants activate STAT3. It concludes that STAT3 activation and the inflammatory tumour phenotype can occur through these mutations. The claim does not imply that all such tumours have them. (LLM, conf=0.92)

  cites [272] Rebouissou, 2009, Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours, Nature source

In the paper

“Therefore, amplification of the IL-6–STAT3 axis is augmented by several pathways after the induction of other STAT3 and NF-κB activators during inflammation processes (Fig. 3) (41, 66).”

What the sources say

• Supported

  In “The view from the mountaintop” (page not provided), the paper describes an IL-6 amplifier driven by interactions between STAT3 and NF-κB. It says several different events can activate that amplifier through STAT3 and/or NF-κB in nonimmune tissues, supporting the citing sentence’s paraphrase. (LLM, conf=0.87)

  cites [41] Hirano, 2010, Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir, Proc. Jpn Acad. Ser. B. Phys. Biol. Sci. source
• Partly supported

  The Discussion reports that IL-17A and IL-6 synergistically increase IL-6 expression through NF-κB and STAT3, establishing a feedback loop. The paper also proposes that other factors may enhance this amplifier, but it does not establish the claimed augmentation by several pathways following induction of other STAT3 and NF-κB activators during inflammation. (LLM, conf=0.83)

  cites [66] Ogura, 2008, Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction, Immunity sourceExperimental — accuracy not yet measured

In the paper

“In addition, the correlation between IL-6 and the prognosis of 23 different cancer types was demonstrated (262).”

What the sources say

• Supported

  The Results section (“Serum IL-6 and survival”) reports a significant association between serum IL-6 and survival in 82 of 101 series, covering 23 cancer types. This supports the citing sentence’s broad claim about a correlation with prognosis, though the finding was not significant in every series. (LLM, conf=0.94)

  cites [262] Lippitz, 2016, Cytokine patterns in cancer patients: a review of the correlation between interleukin 6 and prognosis, Oncoimmunology source

In the paper

“STAT3 directly binds to the IL-6 promoter to induce IL-6 gene expression (82, 83).”

What the sources say

• Supported

  The results section states that STAT3 binds directly to IL6 promoter sequences and activates IL6 transcription. Figure 4 reports a STAT3 chromatin immunoprecipitation assay and reduced reporter activity when candidate binding sites were mutated. (LLM, conf=0.94)

  cites [82] Yoon, 2010, STAT3 transcriptional factor activated by reactive oxygen species induces IL6 in starvation-induced autophagy of cancer cells, Autophagy source
• Supported

  The “Stat3–IL-6 Feed-Forward Loop Regulates Mammary Tumorigenesis” section reports ChIP evidence of Stat3 binding to the IL-6 promoter in 4175 breast cancer cells. It also reports reduced IL-6 expression after Stat3 silencing, supporting the claim that Stat3 promotes IL-6 gene expression in those cells. (LLM, conf=0.91)

  cites [83] Chang, 2013, The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis, Neoplasia source

In the paper

“It was also reported that IL-6R is associated with asthma and atopic dermatitis (270, 271).”

What the sources say

• Partly supported

  The Discussion reports an association between IL6R and asthma risk. It attributes the atopic dermatitis association to a different locus, chromosome 11q13.5, not to IL6R. Page numbers are not available in our copy. (LLM, conf=0.90)

  cites [270] Ferreira, 2011, Identification of IL6R and chromosome 11q13.5 as risk loci for asthma, Lancet sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [271] Esparza-Gordillo, 2013, A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis, J. Allergy Clin. Immunol. source

In the paper

“Consistent with the concept that IL-6 Amp activation in non-immune cells plays a pivotal role in the development of autoimmune diseases, mice devoid of STAT3 or gp130 in non-immune cells like type-1 collagen positive cells are highly resistant to F759 arthritis and EAE (54, 66).”

What the sources say

• Partly supported

  The Results (page unavailable) report significantly suppressed clinical EAE scores in mice lacking gp130 or STAT3 in type 1 collagen-positive cells, supporting the EAE portion. The Introduction mentions F759 arthritis as a disease associated with IL-6 amplifier activation, but this paper does not report that these mutant mice resist F759 arthritis. (LLM, conf=0.85)

  cites [54] Arima, 2012, Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier, Cell sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page unavailable) reports that deleting STAT3 in type I collagen-positive fibroblasts suppressed arthritis in F759 mice. The EAE passage (page unavailable) reports at least partial suppression after STAT3 deletion, but in a Th17-transfer model using otherwise wild-type mice. The paper does not show gp130 deletion in those cells or establish that the mice were highly resistant to both diseases. (LLM, conf=0.87)

  cites [66] Ogura, 2008, Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction, Immunity sourceExperimental — accuracy not yet measured

In the paper

“Furthermore, NF-κB and STAT3 play crucial roles in cancer development and progression (19, 25, 67, 279).”

What the sources say

• Supported

  The “STAT3–NF-κB in cancer inflammation” section explicitly says both have crucial roles in inflammatory responses that promote cancer development and growth. The Abstract also links their persistent activation to malignant progression. No page numbers are provided in the supplied copy. (LLM, conf=0.94)

  cites [19] Yu, 2009, STATs in cancer inflammation and immunity: a leading role for STAT3, Nat. Rev. Cancer source
• Partly supported

  The Introduction describes STAT3 signaling as a major pathway driving cellular transformation, proliferation, invasion and metastasis in cancer. Section 4 mentions NF-κB as involved in PD-L1 expression in melanoma, but does not establish the broader claim that NF-κB plays a crucial role in cancer development and progression generally. No page numbers are available in our copy. (LLM, conf=0.85)

  cites [25] Rebe, 2019, STAT3, a master regulator of anti-tumor immune response, Cancer sourceExperimental — accuracy not yet measured
• Supported

  The Introduction says NF-κB and STAT3 play pivotal roles in tumorigenesis across a number of malignancies. The Abstract explicitly says they cooperate to promote the development and progression of colon, gastric, and liver cancers, supporting the citing sentence’s broad paraphrase. (LLM, conf=0.94)

  cites [67] Grivennikov, 2010, Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer, Cytokine Growth Factor Rev. source

In the paper

“Furthermore, IL-6 and IL-17 or TNFα synergistically enhance the production of various pro-inflammatory mediators including IL-6 from non-immune cells in a manner dependent on STAT3 and NF-κB (66).”

What the sources say

• Partly supported

  The Discussion reports that IL-17A and IL-6 synergistically increased IL-6 and other inflammatory mediators in mouse embryonic fibroblasts through NF-κB and STAT3 signaling. The paper only suggests that TNF-α may enhance the IL-6 amplifier; it does not establish the claimed IL-6–TNF-α synergy or its dependence on those pathways. (LLM, conf=0.89)

  cites [66] Ogura, 2008, Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction, Immunity sourceExperimental — accuracy not yet measured

In the paper

“The produced IL-6 further induces Th17 cell differentiation through STAT3 in the presence of TGFβ, IL-1β and IL-23, all of which are rich in inflammatory lesions and tumor microenvironments (164, 166, 169–171, 174, 175).”

What the sources say

• ?Not checked — no full text of the sourcecites [164] Veldhoen, 2006, TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells, Immunity source
• ?Not checked — no full text of the sourcecites [166] Bettelli, 2006, Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells, Nature source
• ?Not checked — no full text of the sourcecites [169] Acosta-Rodriguez, 2007, Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells, Nat. Immunol. source
• ?Not checked — no full text of the sourcecites [170] Wilson, 2007, Development, cytokine profile and function of human interleukin 17-producing helper T cells, Nat. Immunol. source
• Partly supported

  The paper’s main text (indexed under Abstract; page unavailable) says IL-6 acts through STAT3 and supports Th17 differentiation with TGF-β, or with IL-1β and IL-23 independently of TGF-β. It does not establish that all four cytokines act together as the sentence implies: it reports that TGF-β inhibits IL-23 receptor expression. It says TGF-β is present at sites of inflammation, but does not establish that all four cytokines are abundant there or in tumor microenvironments. (LLM, conf=0.87)

  cites [171] Ghoreschi, 2010, Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling, Nature sourceExperimental — accuracy not yet measured

In the paper

“Although the development of F759 arthritis is dependent on Th17 cells, the F759 mutation is required in non-immune cells but not immune cells, clearly indicating that the interaction between non-immune cells and immune cells is crucial for arthritis development in F759 mice (66, 99).”

What the sources say

• Partly supported

  The Discussion reports that F759 arthritis is dependent on IL-17A: deleting IL-17A significantly reduced arthritis scores, and overexpressing it induced arthritis. The paper also reports increased Th17 cells in older F759 mice, but these findings do not establish that Th17 cells themselves are required for arthritis development. (LLM, conf=0.86)

  cites [66] Ogura, 2008, Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction, Immunity sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section reports that MHCII-restricted CD4+ T cells are necessary for F759 arthritis. It does not establish that the disease depends specifically on the Th17 subset; searches for “Th17” and “IL-17-producing T helper cells” found no such finding in our copy. Page numbers were not available. (LLM, conf=0.85)

  cites [99] Sawa, 2006, Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4+ T cells, J. Exp. Med. sourceExperimental — accuracy not yet measured

In the paper

“NF-κB also increases IL-6 levels by inhibiting let-7 expression (89).”

What the sources say

• Supported

  The Discussion section, “A molecular pathway that links inflammation to cellular transformation,” explicitly states that NF-κB activation and subsequent repression of let-7 increase IL6 levels. It also explains that NF-κB inhibits let-7 primarily by activating Lin28B, so the claimed effect is indirect. (LLM, conf=0.94)

  cites [89] Iliopoulos, 2009, An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation, Cell source

In the paper

“In addition, STAT3 activates NF-κB through the direct induction of miR-21 and miR-181b-1, leading to IL-6 gene expression (90).”

What the sources say

• Supported

  The Introduction states that STAT3 directly activates miR-21 and miR-181b-1 and that their inhibition of PTEN and CYLD leads to NF-κB activation. The Results sections on PTEN and CYLD report that these pathways affect IL6 production or expression, identifying IL6 as an NF-κB target gene. No page numbers are provided in the supplied copy. (LLM, conf=0.92)

  cites [90] Iliopoulos, 2010, STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer, Mol. Cell source

In the paper

“Genome-wide association studies (GWAS), meta-analysis, exome analysis and single nucleotide polymorphism (SNP) mapping have associated IL-6, IL-6R and gp130 with inflammatory diseases such as RA and coronary artery disease (263–269).”

What the sources say

• ?Not checked — no full text of the sourcecites [263] Dar, 2017, Interleukin-6-174G > C (rs1800795) polymorphism distribution and its association with rheumatoid arthritis: a case-control study and meta-analysis, Autoimmunity source
• ?Not checked — no full text of the sourcecites [264] Hou, 2015, Association of interleukin-6 gene polymorphism with coronary artery disease: an updated systematic review and cumulative meta-analysis, Inflamm. Res. source
• Partly supported

  The Discussion (page not specified) reports that an IL6R variant was associated with reduced coronary heart disease risk, and the Methods describe analysis of IL6R SNPs. The paper discusses rheumatoid arthritis in connection with tocilizumab trials, but does not report genetic associations linking IL6 or gp130 to rheumatoid arthritis, or exome analyses establishing the broader claim. (LLM, conf=0.88)

  cites [265] Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium, 2012, The interleukin-6 receptor as a target for prevention of coronary heart disease: a Mendelian randomisation analysis, Lancet sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract and Results (page numbers not provided) report a meta-analysis and case-control study associating IL-6 SNPs with rheumatoid arthritis. These passages do not support attributing associations involving IL-6R, gp130, or coronary artery disease—or findings from GWAS or exome analysis—to this paper. (LLM, conf=0.88)

  cites [266] Li, 2014, Association between interleukin-6 gene polymorphisms and rheumatoid arthritis in Chinese Han population: a case-control study and a meta-analysis, Sci. Rep. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section (“Human genetic association of polymorphisms in the IL6ST/gp130 gene”; page unavailable) reports an association between an IL6ST/gp130 SNP and coronary artery disease, supporting the SNP-mapping portion of the claim. The passages do not establish associations for IL-6 or IL-6R, rheumatoid arthritis, or findings from GWAS, meta-analysis, or exome analysis. (LLM, conf=0.88)

  cites [267] Luchtefeld, 2007, Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man, J. Exp. Med. sourceExperimental — accuracy not yet measured
• Partly supported

  The paper’s Abstract (page unavailable) reports a GWAS meta-analysis of rheumatoid arthritis risk loci and identifies the IL-6R-targeting drug tocilizumab among therapies linked to its RA genetics analysis. It does not establish the claimed genetic associations for IL-6, IL-6R and gp130 across both RA and coronary artery disease, or report exome analysis supporting them. (LLM, conf=0.83)

  cites [268] Okada, 2014, Genetics of rheumatoid arthritis contributes to biology and drug discovery, Nature sourceExperimental — accuracy not yet measured
• Partly supported

  The paper’s Abstract reports a GWAS meta-analysis associating SNPs near IL6ST with rheumatoid arthritis and identifies gp130 as the IL6ST protein product. It also says IL6ST lies outside the region of linkage disequilibrium with the associated SNPs, so it does not establish a gp130 association. The cited passages do not support associations for IL-6 or IL-6R, coronary artery disease, or exome analysis. (LLM, conf=0.86)

  cites [269] Stahl, 2010, Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci, Nat. Genet. sourceExperimental — accuracy not yet measured

In the paper

“On the other hand, the frequency of a polymorphism at the 5’ flanking region of the IL-6 gene that is correlated with lower levels of plasma IL-6 is reduced in systemic-onset juvenile chronic arthritis (275).”

What the sources say

• Partly supported

  The Abstract reports that the −174C allele is associated with lower plasma IL-6 in healthy subjects. Table IV and the accompanying results report a reduced CC genotype frequency in patients whose arthritis began at age 5 or younger, but no significant reduction in C-allele frequency in any patient group. The claim omits that genotype and age-of-onset qualification. Page numbers are not indicated in our copy. (LLM, conf=0.90)

  cites [275] Fishman, 1998, The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis, J. Clin. Invest. sourceExperimental — accuracy not yet measured

In the paper

“Murakami et al. demonstrated that local initiators such as microbleeding induce the accumulation of T cells in the joints through CCL20 production (52).”

What the sources say

• Supported

  The Results section on CCL20 states that local microbleeding induces CCL20 expression in joints, causing accumulation of CCR6+ Th17 cells. The experiments described there used F759 mice that had received Th17-cell transfers; no page number is provided in our copy. (LLM, conf=0.93)

  cites [52] Murakami, 2011, Local microbleeding facilitates IL-6- and IL-17-dependent arthritis in the absence of tissue antigen recognition by activated T cells, J. Exp. Med. source

In the paper

“In an adoptive transfer model of EAE using myelin-specific autoreactive CD4(+) T cells, it was found that the initial invasion site of these cells is determined by specific neural activation through the sensory–sympathetic pathway stimulated by gravity (54).”

What the sources say

• Supported

  The Results describe passive transfer of MOG-specific pathogenic CD4+ T cells to induce EAE and identify the fifth lumbar cord as their early CNS entry site. Further Results passages show that soleus-muscle sensory activation creates this entry gateway; the Discussion explains that sensory activation recruits sympathetic neurons and links the process to antigravity soleus-muscle activity. Page numbers are unavailable in our copy. (LLM, conf=0.93)

  cites [54] Arima, 2012, Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier, Cell source

In the paper

“Importantly, senescent cells and tissues contribute to age-related pathologies including cancer by producing inflammatory cytokines such as IL-6, which act as autocrine and paracrine factors (7).”

What the sources say

• Partly supported

  The Discussion (page not provided) reports that senescent cells secrete IL-6 that can act in both autocrine and paracrine fashions, and connects this inflammatory response to cancer. The paper studies oncogene-induced senescence and does not establish that senescent cells or tissues contribute to age-related pathologies more broadly. (LLM, conf=0.86)

  cites [7] Kuilman, 2008, Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network, Cell sourceExperimental — accuracy not yet measured

In the paper

“Concerning age-related diseases, senescent cells themselves are critically involved in T1D and T2D, and the deletion of senescent beta cells prevents diabetes (57, 298), indicating that even in T1D in which tissue-specific T cells are involved (299–301), local initiators originating from senescent beta cells play critical roles.”

What the sources say

• Supported

  The citation (299–301) is attached to the clause about tissue-specific T cells, not to the citing authors’ inference about senescent beta cells. In “Pathophysiology of type 1 diabetes in mouse and human,” the paper reports that islet-antigen-reactive T cells occur in both NOD mice and people with type 1 diabetes and play a dominant role in disease initiation and progression. (LLM, conf=0.93)

  cites [299] Bluestone, 2010, Genetics, pathogenesis and clinical interventions in type 1 diabetes, Nature source
• ?Not checked — no full text of the sourcecites [300] Wållberg, 2013, Immune mechanisms in type 1 diabetes, Trends Immunol. source
• Supported

  The citation to this source is attached to the claim that tissue-specific T cells are involved in T1D. The section on insulitis and antigen specificity reports autoreactive CD8+ T cells in patients’ islets, while noting that most T cells in the lesion are not islet-specific. The statement about initiators from senescent beta cells is the citing authors’ inference, not a claim attributed to this source. (LLM, conf=0.91)

  cites [301] Christoffersson, 2016, Recent advances in understanding type 1 diabetes, F1000Res. source

In the paper

“These results suggest even T-cell-dependent tissue-specific autoimmune diseases do not necessarily require antigen-specific T cells (52).”

What the sources say

• Supported

  The Discussion proposes a model for certain MHC class II–mediated tissue-specific autoimmune diseases in which T-cell activation occurs regardless of antigen specificity. It also reports that arthritis in F759 mice depends on activated CD4+ T cells but does not support a requirement for their recognition of tissue antigen. (LLM, conf=0.91)

  cites [52] Murakami, 2011, Local microbleeding facilitates IL-6- and IL-17-dependent arthritis in the absence of tissue antigen recognition by activated T cells, J. Exp. Med. source

In the paper

“This neural pathway, which is now called the gateway reflex (286, 287), activates the IL-6 Amp through beta-adrenergic receptors in the dorsal vessels of the fifth lumbar cord, allowing for autoreactive T-cell accumulation and disease onset (54).”

What the sources say

• Partly supported

  The Results report that neural activation increases IL-6 amplifier activity in fifth-lumbar dorsal vessels, promoting pathogenic T-cell accumulation; atenolol suppresses that accumulation and abrogates EAE development. The copy identifies atenolol as a norepinephrine antagonist but does not establish that the pathway acts specifically through beta-adrenergic receptors in those vessels. (LLM, conf=0.82)

  cites [54] Arima, 2012, Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier, Cell sourceExperimental — accuracy not yet measured
• Partly supported

  The Fig. 1 caption and “Gravity is a positive regulator of local inflammation” section describe norepinephrine enhancing the inflammation amplifier at L5 dorsal vessels, recruiting pathogenic CD4+ T cells in a preclinical EAE mouse model. The section also reports that blocking adrenergic receptors reduced chemokine expression and EAE severity, but it does not specify beta-adrenergic receptors for this pathway. The claim’s receptor subtype is therefore not established by this copy. (LLM, conf=0.85)

  cites [286] Kamimura, 2018, Gateway reflex: neural activation-mediated immune cell gateways in the central nervous system, Int. Immunol. sourceExperimental — accuracy not yet measured
• Partly supported

  The Efferent Autonomic Neurons and Neural Reflexes section (page not provided) describes a gateway reflex in an animal model of multiple sclerosis: catecholamine release at L5 dorsal blood vessels stimulates an IL-6-amplifying mechanism and increases autoreactive T-cell entry into the CNS. It does not specify β-adrenergic receptors in those vessels or state that the reflex causes disease onset. (LLM, conf=0.88)

  cites [287] Pavlov, 2018, Molecular and functional neuroscience in immunity, Annu. Rev. Immunol. sourceExperimental — accuracy not yet measured

In the paper

“Further, pain sensation induces a relapse of EAE by activating the IL-6 Amp through another sensory–sympathetic neural network (55).”

What the sources say

• Supported

  The Introduction reports that pain induced relapse in EAE-recovered mice through sensory-mediated sympathetic activation. The Discussion describes inflammation-amplifier activation involving IL-6 as a downstream step critical to pain-mediated EAE relapse. Our copy provides section labels but no page numbers. (LLM, conf=0.91)

  cites [55] Arima, 2015, A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model, Elife source

In the paper

“Target molecules of the IL-6 Amp include EGFR, c-Myc, Pim1, VEGFα, hypoxia-inducible factor 1-alpha (HIF1-α), MMPs and many pro-inflammatory cytokines and growth factors involved in cell survival, proliferation, angiogenesis and metastasis (Fig. 3) (10, 11).”

What the sources say

• Partly supported

  The Results report that IL-6 stimulation increased ErbB1 (EGFR) expression, and the Discussion says IL-6 amplifier activation induces chemokines and pro-inflammatory cytokines. Our copy does not substantiate the listed c-Myc, Pim1, VEGFα, HIF1-α, or MMPs as amplifier targets, or the asserted roles in cell survival, proliferation, angiogenesis, and metastasis (searched those terms). (LLM, conf=0.87)

  cites [10] Murakami, 2013, Disease-association analysis of an inflammation-related feedback loop, Cell Rep. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [11] Atsumi, 2014, Inflammation amplifier, a new paradigm in cancer biology, Cancer Res. source

In the paper

“Lysophospholipid sphingosine-1-phosphate (S1P), a lipid metabolite, activates STAT3 through its G protein-coupled receptor, S1P receptor-1 (309).”

What the sources say

• Supported

  The paper identifies S1PR1 as a G-protein-coupled receptor for S1P (introductory text labeled Abstract in our copy). In Results, “S1pr1-mediated Stat3 activation is persistent,” S1P treatment induced Stat3 activation, and the effect was more pronounced in cells expressing more S1PR1. (LLM, conf=0.94)

  cites [309] Lee, 2010, STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors, Nat. Med. source

In the paper

“F759 mice bred by mating T-cell antigen-receptor transgenic mice and Rag2-KO mice to express only one T-cell antigen-receptor on CD4(+) T cells still develop arthritis.”

What the sources say

• Supported

  The Results section (‘Cognate antigen recognition by CD4+ T cells is not required’) reports that F759 mice with a single T-cell receptor variant on a RAG-deficient background developed arthritis. Figure 1 identifies the tested mice as RAG2−/− F759-P25 and RAG2−/− F759-OT2. (LLM, conf=0.92)

  cites [52] Murakami, 2011, Local microbleeding facilitates IL-6- and IL-17-dependent arthritis in the absence of tissue antigen recognition by activated T cells, J. Exp. Med. source

In the paper

“Consistent with the notion that severe COVID-19 is a cytokine storm syndrome (12–17, 336), the severity of COVID-19 is associated with an increased level of inflammatory cytokines, such as IL-6, granulocyte macrophage colony-stimulating factor (GM-CSF) and TNFα (333, 337).”

What the sources say

• Partly supported

  The Discussion reports higher TNFα concentrations in patients requiring ICU care than in those who did not, linking elevated cytokines with disease severity. It names GCSF, not GM-CSF, in that comparison; the Methods list GCSF and GMCSF separately. The paper also does not identify IL-6 as higher in its ICU patients. (LLM, conf=0.90)

  cites [333] Huang, 2020, Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Lancet sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Table 3; page unavailable) report elevated IL-6 in 51 of 99 patients, and the Discussion describes a cytokine storm. The paper does not link IL-6 levels to disease severity or report levels of GM-CSF or TNFα, so it supports only part of the attributed claim. (LLM, conf=0.88)

  cites [337] Chen, 2020, Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study, Lancet sourceExperimental — accuracy not yet measured

In the paper

“Its expression in breast cancer activates an IL-6 autocrine signaling loop to activate STAT3, which is critical for tumorigenesis (321).”

What the sources say

• Supported

  The Discussion (page not provided) states that HER2 overexpression induces IL-6 secretion and that secreted IL-6 is critical for HER2-mediated oncogenesis through autocrine activation of Stat3 in tumor cells. The Results also describe a HER2-driven autocrine IL-6–Stat3 signaling complex. (LLM, conf=0.94)

  cites [321] Hartman, 2011, HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis, Cancer Res. source

In the paper

“Consistent with the notion that severe COVID-19 is a cytokine storm syndrome (12–17, 336), the severity of COVID-19 is associated with an increased level of inflammatory cytokines, such as IL-6, granulocyte macrophage colony-stimulating factor (GM-CSF) and TNFα (333, 337).”

What the sources say

• Partly supported

  The opening paragraph says that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. The concluding paragraph likewise recommends screening severe patients to identify that subgroup. The cited paper does not establish that severe COVID-19 generally is a cytokine storm syndrome. (LLM, conf=0.89)

  cites [12] Mehta, 2020, COVID-19: consider cytokine storm syndromes and immunosuppression, Lancet sourceExperimental — accuracy not yet measured
• Supported

  The 'Targeting cytokine storm' conclusion describes an observed cytokine storm in severe COVID-19. The Introduction likewise discusses an out-of-control cytokine response in severe COVID-19 patients. Together, these passages support the cited notion. (LLM, conf=0.90)

  cites [13] Mahmudpour, 2020, COVID-19 cytokine storm: the anger of inflammation, Cytokine source
• ?Not checked — no full text of the sourcecites [14] Hu, 2021, The cytokine storm and COVID-19, J. Med. Virol. source
• Supported

  The Main Text states that ARDS seen with SARS-CoV-2 infection is a cytokine release syndrome induced by cytokine storms. It also describes this severe manifestation as a major phenotype of COVID-19, supporting the cited notion. (LLM, conf=0.93)

  cites [15] Hirano, 2020, COVID-19: a new virus, but a familiar receptor and cytokine release syndrome, Immunity source
• Partly supported

  The Clinical-Immunogical Spectrum of COVID-19 section says that immune-response failure can at times lead to cytokine release syndrome with severe inflammation. The Adaptive Immune Response section likewise says a dysfunctional response may lead to a cytokine storm. These passages support the cited notion, but not the unqualified statement that severe COVID-19 is always a cytokine storm syndrome; page numbers were not available in our copy. (LLM, conf=0.82)

  cites [16] García, 2020, Immune response, inflammation, and the clinical spectrum of COVID-19, Front. Immunol. sourceExperimental — accuracy not yet measured
• Supported

  The Predictors of COVID-19 Disease Risk and Severity section describes severe cases as having features reminiscent of cytokine release syndromes, including marked systemic cytokine release. The Therapeutic Immunomodulation section also explicitly discusses a cytokine storm in COVID-19 patients and calls it COVID-19-associated CRS. Those passages support the citing sentence’s framing as a notion, rather than a definitive classification of every severe case. (LLM, conf=0.88)

  cites [17] Vabret, 2020, Immunology of COVID-19: current state of the science, Immunity source
• Partly supported

  The “COVID-19 and Cytokine Storms” section reports elevated cytokines in severely ill patients, which supports a possible link. But it says it is unclear whether those levels become pathological and calls for identifying patients who develop a bona fide cytokine storm; it does not establish that severe COVID-19 is a cytokine storm syndrome. Page numbers were not supplied. (LLM, conf=0.86)

  cites [336] Mangalmurti, 2020, Cytokine storms: understanding COVID-19, Immunity sourceExperimental — accuracy not yet measured

In the paper

“Similarly, activated mutant EGFR in lung cancer induces IL-6 gene expression to activate constitutive IL-6–STAT3 signaling in a paracrine and autocrine manner (257).”

What the sources say

• Supported

  The IL-6 transcription Results show that mutant EGFR contributes to IL-6 gene activation. The Results also show that blocking IL-6 reduces STAT3 phosphorylation in the lung cancer cells, while their conditioned medium activates STAT3 in other cells, supporting autocrine and paracrine signaling. The indexed passages do not provide page numbers. (LLM, conf=0.90)

  cites [257] Gao, 2007, Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas, J. Clin. Invest. source

In the paper

“Mutated K-RAS activates NF-κB in a mouse model of lung cancer (315), and the K-RAS-induced activation of NF-κB is required for pancreatic cancer development (316), which depends on IL-6 trans-signaling-mediated STAT3 activation (317).”

What the sources say

• Supported

  The Results section (‘NF-κB is activated in mouse K-Ras-induced lung cancers’) reports higher NF-κB reporter activity in K-RasG12D lung tumors than in controls. The Discussion explicitly concludes that K-Ras triggers NF-κB activation in a mouse model of lung cancer in situ. (LLM, conf=0.95)

  cites [315] Bassères, 2010, Requirement of the NF-kappaB subunit p65/RelA for K-Ras-induced lung tumorigenesis, Cancer Res. source

In the paper

“Exosomal miR-1247-3p secreted by hepatocellular carcinoma activates beta1-integrin–NF-κB signaling in fibroblasts, resulting in the production of pro-inflammatory cytokines, including IL-6 and IL-8 (323).”

What the sources say

• Supported

  The Discussion states that tumor-derived exosomal miR-1247-3p activates β1-integrin–NF-κB signaling in fibroblasts and that the resulting cancer-associated fibroblasts secrete more IL-6 and IL-8. The Results section, “Activated fibroblasts promote liver cancer progression,” also reports increased IL-6 and IL-8 secretion after miR-1247-3p treatment. No page numbers are provided in our copy. (LLM, conf=0.94)

  cites [323] Fang, 2018, Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer, Nat. Commun. source

In the paper

“This process is critically involved in colitis-associated cancer (310).”

What the sources say

• Supported

  The Discussion states that the SphK1/S1P pathway and its downstream amplification loop play an essential role in chronic inflammation and the development of colitis-associated cancer. The citing sentence does not identify what “this process” refers to, but the paper directly supports that characterization of the process it studies. (LLM, conf=0.90)

  cites [310] Liang, 2013, Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer, Cancer Cell. source

In the paper

“It confers pancreatic cancer cell resistance to TNFα-induced apoptosis through NF-κB activation and the enhanced expression of IL-6 (319).”

What the sources say

• Supported

  The Background states that MSLN overexpression leads to constitutive NF-κB activation and resistance to TNF-α-mediated cytotoxicity in pancreatic cancer cells. The Results section on IL-6 reports increased IL-6 production in MSLN-overexpressing cells and greater TNF-α-induced apoptosis when IL-6 was silenced. Page numbers are not provided in our copy. (LLM, conf=0.94)

  cites [319] Bharadwaj, 2011, Mesothelin confers pancreatic cancer cell resistance to TNF-α-induced apoptosis through Akt/PI3K/NF-κB activation and IL-6/Mcl-1 overexpression, Mol. Cancer source

In the paper

“In addition to NF-κB activation, TLRs such as TLR2, TLR4, TLR7 and TLR9 activate STAT3 (206, 325).”

What the sources say

• Partly supported

  The Results section (‘Direct and rapid induction of Stat3 activity in DCs’; page unavailable) reports STAT3 activation by the TLR4 agonist LPS and by CpG, which the paper identifies as acting through TLR9. The passages do not establish that TLR2 or TLR7 activate STAT3, so this source supports only two of the four receptors listed. (LLM, conf=0.88)

  cites [206] Kortylewski, 2009, Toll-like receptor 9 activation of signal transducer and activator of transcription 3 constrains its agonist-based immunotherapy, Cancer Res. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [325] Yu, 2014, Revisiting STAT3 signalling in cancer: new and unexpected biological functions, Nat. Rev. Cancer source

In the paper

“Another oncogenic molecule, BRAFE600, induces IL-6 and IL-1, a NF-κB activator, through C/EBPβ (7).”

What the sources say

• Partly supported

  In “C/EBPβ Is a Critical Regulator of IL-6 in OIS” (page unavailable), the paper says oncogenic stress activates IL6 and IL1B and identifies C/EBPβ as a regulator of these inflammatory genes. It also shows that C/EBPβ depletion reduces IL-6. The retrieved passages do not describe IL-1 as an NF-κB activator, so that part of the sentence is unsupported by our copy. (LLM, conf=0.86)

  cites [7] Kuilman, 2008, Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network, Cell sourceExperimental — accuracy not yet measured

In the paper

“Among the elevated inflammatory mediators, the blood IL-6 level is highly correlated with the disease mortality (293, 338) and predicts the need for mechanical ventilation (339).”

What the sources say

• Supported

  The Abstract’s Conclusion states that the maximal IL-6 level was highly predictive of the need for mechanical ventilation in patients with COVID-19. The cited source supports the ventilation claim; the mortality claim has separate citations. (LLM, conf=0.94)

  cites [339] Herold, 2020, Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19, J. Allergy Clin. Immunol. source

In the paper

“Therefore, SARS-CoV-1 and SARS-CoV-2 infection activate both NF-κB and STAT3, key elements of the IL-6 Amp, to cause cytokine storm (12, 13, 15, 349, 350).”

What the sources say

• Partly supported

  The paper’s main text (page not available in our copy) says that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome and reports elevated IL-6 among predictors of fatality. It does not say that SARS-CoV-1 or SARS-CoV-2 activates NF-κB and STAT3, or identify an IL-6 Amp mechanism causing the storm. (LLM, conf=0.88)

  cites [12] Mehta, 2020, COVID-19: consider cytokine storm syndromes and immunosuppression, Lancet sourceExperimental — accuracy not yet measured
• Partly supported

  The ACE/Angiotensin II/AT1R axis section describes SARS-CoV-2 activating NF-κB and STAT3, with their simultaneous activation driving the IL-6 amplifier and cytokine storm. The copy does not extend that mechanism to SARS-CoV-1; its Introduction mentions SARS-CoV in connection with immune responses, not this pathway. Page numbers were not provided. (LLM, conf=0.88)

  cites [13] Mahmudpour, 2020, COVID-19 cytokine storm: the anger of inflammation, Cytokine sourceExperimental — accuracy not yet measured
• Partly supported

  The Main Text says SARS-CoV-2 infection can activate NF-κB and STAT3 and thereby activate the IL-6 amplifier; it also describes COVID-19 cytokine release syndrome as possibly involving that amplifier. It discusses SARS-CoV-associated ACE2 loss and lung injury, but does not say that SARS-CoV-1 activates both pathways through the IL-6 amplifier. The claim also states the proposed cytokine-storm mechanism more definitively than the source does. Page numbers are not provided in our copy. (LLM, conf=0.87)

  cites [15] Hirano, 2020, COVID-19: a new virus, but a familiar receptor and cytokine release syndrome, Immunity sourceExperimental — accuracy not yet measured

In the paper

“Macrophage activation via TLR4, a type of PRR, is also involved in gastric acid-induced ARDS and mouse ARDS models induced by SARS-CoV-1 or influenza virus H5N1 (355).”

What the sources say

• Partly supported

  The Results sections on acid-induced ALI and inactivated H5N1-induced ALI show TLR4-dependent lung injury and macrophage cytokine responses in mice. For SARS, the paper reports oxidized phospholipids in patients’ lungs, but does not establish TLR4-mediated macrophage activation in a SARS-induced mouse ARDS model. The H5N1 experiment used inactivated virus. Page numbers were not available in our copy. (LLM, conf=0.88)

  cites [355] Imai, 2008, Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury, Cell sourceExperimental — accuracy not yet measured

In the paper

“The anti-IL-6R antibody tocilizumab is effective at treating patients with CAR-T-induced cytokine release syndrome (CRS) (352, 364) and is being considered for treating ARDS in COVID-19 patients (365–368).”

What the sources say

• Supported

  The ‘IL-6 and IL-6R antagonists’ section says tocilizumab is used to manage CRS after CAR-T-cell therapy and that it rapidly reverses CRS symptoms in most patients. The clinical case study also identifies it as an anti-IL-6R antibody and reports a prompt response. The claim does not attribute the separate COVID-19 statement to this source. (LLM, conf=0.94)

  cites [352] Neelapu, 2018, Chimeric antigen receptor T-cell therapy—assessment and management of toxicities, Nat. Rev. Clin. Oncol. source
• Supported

  The Results (Cytokine-Release Syndrome) report that nine patients received tocilizumab for severe CRS after CAR-T therapy, with rapid improvement and full recovery. The paper’s Results summary explicitly describes severe CRS as effectively treated with the anti–IL-6 receptor antibody tocilizumab. (LLM, conf=0.94)

  cites [364] Maude, 2014, Chimeric antigen receptor T cells for sustained remissions in leukemia, N. Engl. J. Med. source

In the paper

“In addition to this PRR-mediated activation of NF-κB, the nucleocapsid protein of SARS-CoV-1 activates IL-6 expression through NF-κB by facilitating the translocation of NF-κB from the cytosol to the nucleus (341).”

What the sources say

• Supported

  The Discussion reports that SARS-CoV N protein facilitates translocation of p65, an NF-κB subunit, from the cytosol to the nucleus. It also reports that NF-κB activity is involved in N-protein-induced IL-6 expression. (LLM, conf=0.95)

  cites [341] Zhang, 2007, Nucleocapsid protein of SARS-CoV activates interleukin-6 expression through cellular transcription factor NF-kappaB, Virology source

In the paper

“Of note, aging, obesity and inflammation-related diseases such as diabetes and cardiovascular diseases have been shown to be risk factors for the severity of COVID-19 (293, 371–373).”

What the sources say

• Partly supported

  The Discussion identifies older age as a risk factor for in-hospital death among adults hospitalised with COVID-19. Table 1 in the Results shows diabetes and coronary heart disease were more common among non-survivors than survivors, but it does not establish them as independent risk factors for disease severity. The paper does not report obesity as a risk factor. (LLM, conf=0.88)

  cites [293] Zhou, 2020, Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study, Lancet sourceExperimental — accuracy not yet measured
• Partly supported

  The letter’s Table 2 and accompanying text report that obesity was associated with greater COVID-19 severity in patients with MAFLD, even after adjustment for age and diabetes (page not specified in our copy). They do not establish aging, diabetes, or cardiovascular disease as independent risk factors; the broader population claim also exceeds the study’s MAFLD cohort. (LLM, conf=0.88)

  cites [371] Zheng, 2020, Letter to the Editor: obesity as a risk factor for greater severity of COVID-19 in patients with metabolic associated fatty liver disease, Metabolism sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract Results and Discussion report that patients with diabetes had more severe COVID-19 pneumonia and a poorer prognosis. The Discussion links diabetes and obesity to inflammation, and the Results note cardiovascular disease among patients with diabetes, but the paper does not establish aging, obesity, or cardiovascular disease individually as risk factors for COVID-19 severity. Page numbers are not provided in our copy. (LLM, conf=0.88)

  cites [372] Guo, 2020, Diabetes is a risk factor for the progression and prognosis of COVID-19, Diabetes Metab. Res. Rev. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [373] Clerkin, 2020, COVID-19 and cardiovascular disease, Circulation source

In the paper

“Notably, IL-6 and TNFα serum levels are known to be significant predictors of disease severity and death (340).”

What the sources say

• Supported

  The Results section (“Using cytokines to complement risk stratification”) concludes that IL-6 and TNF-α independently predict both disease severity and survival. The finding concerns patients hospitalized with COVID-19. (LLM, conf=0.94)

  cites [340] Del Valle, 2020, An inflammatory cytokine signature predicts COVID-19 severity and survival, Nat. Med. source

In the paper

“SARS-CoV-1 and MERS-CoV activate NF-κB in a manner dependent on MyD88 through PRRs, such as retinoic acid-inducible gene I protein (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), leading to the activation of a variety of pro-inflammatory cytokines, including IL-6, TNFα, IL-8 and CC-chemokine ligand 2 (CCL2) (335).”

What the sources say

• Partly supported

  The “Immune evasion” passage in The pathogenesis of SARS-CoV and MERS-CoV (page unavailable) describes RIG-I/MDA5 detection, signalling involving MYD88, NF-κB activation, and transcription of pro-inflammatory cytokines. The “Immunopathology” passage names IL-6, IL-8 and CCL2 as elevated in SARS patients, but does not link those specific molecules to this pathway. Our copy does not establish that the pathway is MYD88-dependent or identify TNFα as one of its products. (LLM, conf=0.86)

  cites [335] de Wit, 2016, SARS and MERS: recent insights into emerging coronaviruses, Nat. Rev. Microbiol. sourceExperimental — accuracy not yet measured

In the paper

“The AngII–AT1R axis activates the NF-κB pathway through various growth factors and pro-inflammatory cytokines (347, 348).”

What the sources say

• ?Not checked — no full text of the sourcecites [347] Brasier, 2002, Vascular inflammation and the renin-angiotensin system, Arterioscler. Thromb. Vasc. Biol. source
• Partly supported

  The Ang II-Stimulated ROS Generation section reports that Ang II–AT1R signaling stimulates NF-κB activity in human neutrophils. It does not establish that growth factors or pro-inflammatory cytokines mediate that activation; it says the mechanisms of cytokine effects require further study. The Jak/STAT section discusses cytokine-mediated signaling, but for Jak/STAT rather than NF-κB. (LLM, conf=0.85)

  cites [348] Hunyady, 2006, Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II, Mol. Endocrinol. sourceExperimental — accuracy not yet measured

In the paper

“IL-1 and IL-6 are involved in the lethal cytokine storm sometimes seen in CAR-T treatment (353, 354).”

What the sources say

• ?Not checked — no full text of the sourcecites [353] Norelli, 2018, Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells, Nat. Med. source
• Supported

  The Abstract describes potentially lethal cytokine release syndrome after CAR T-cell infusion and states that its severity in the study's mouse model is mediated by IL-1 and IL-6 produced by recipient macrophages. It also describes severe CRS as a complication of CAR T-cell treatment in patients. (LLM, conf=0.94)

  cites [354] Giavridis, 2018, CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade, Nat. Med. source

In the paper

“Since SARS-CoV-2 uses angiotensin-converting enzyme (ACE) 2 as a receptor (342, 343), it is speculated that SARS-CoV-2 induces pro-inflammatory cytokines through angiotensin II (AngII)/angiotensin type 1 receptor (AT1R) (15) as SARS-CoV-1 does (344–346).”

What the sources say

• Supported

  The Main section reports that 2019-nCoV entered ACE2-expressing cells but not cells without ACE2, indicating that ACE2 is probably its cellular entry receptor. This directly supports the cited claim about SARS-CoV-2, called 2019-nCoV in the paper. (LLM, conf=0.95)

  cites [342] Zhou, 2020, A pneumonia outbreak associated with a new coronavirus of probable bat origin, Nature source
• Supported

  The Results section, “SARS-CoV-2 Employs the SARS-CoV Receptor for Host Cell Entry,” reports that ACE2 expression enabled SARS-CoV-2 entry into otherwise non-susceptible cells and that anti-ACE2 antibodies blocked spike-mediated entry. The Discussion also states that the SARS-CoV-2 spike exploits ACE2 for entry. Page numbers are not provided in our copy. (LLM, conf=0.94)

  cites [343] Hoffmann, 2020, SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Cell source

In the paper

“Furthermore, the ACE1 II genotype is protective against COVID-19 as compared to the ACE1 DD genotype (358), and serum levels of ACE1 are higher in the DD genotype compared with the II genotype (359).”

What the sources say

• Partly supported

  The Results report that countries with higher ACE1 II genotype frequencies had fewer SARS-CoV-2 cases and COVID-19 deaths, and the Discussion predicts greater disease severity in DD carriers. These population-level correlations and predictions are consistent with a protective effect, but the paper does not establish that individuals with the II genotype are protected relative to individuals with the DD genotype; the Conclusions call for clinical outcomes in those carriers to be assessed. (LLM, conf=0.87)

  cites [358] Yamamoto, 2020, SARS-CoV-2 infections and COVID-19 mortalities strongly correlate with ACE1 I/D genotype, Gene sourceExperimental — accuracy not yet measured

In the paper

“Consistent with animal models, it was reported that AngII–AT1R axis inhibitors may be beneficial for COVID-19 patients (360–363) to decrease serum IL-6 levels (360).”

What the sources say

• Partly supported

  The Results report a trend toward lower peripheral-blood IL-6 in the ACEI/ARB group, and the Discussion suggests these drugs may attenuate inflammation through IL-6 inhibition. The study enrolled COVID-19 patients with hypertension; it does not establish an IL-6 decrease in COVID-19 patients generally, and the reported IL-6 finding was a trend rather than a confirmed reduction. (LLM, conf=0.86)

  cites [360] Meng, 2020, Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension, Emerg. Microbes Infect. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Primary Outcomes; page unavailable) associate inpatient ACEI/ARB use with lower mortality among patients with hypertension hospitalized with COVID-19, supporting the possibility of benefit. But our copy does not report that these drugs decrease serum IL-6 levels; searches for “IL-6” and “interleukin-6” found no such finding. (LLM, conf=0.88)

  cites [361] Zhang, 2020, Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19, Circ. Res. sourceExperimental — accuracy not yet measured
• Partly supported

  In the ‘Frequency (%)’ discussion (page unavailable), the paper reports possible benefits of ACE inhibitors and ARBs and cites a small study of COVID-19 patients with hypertension in which IL-6 tended to be lower among users. It does not show that the inhibitors decreased serum IL-6: the IL-6 observation is a reported group comparison, not a measured change or an established treatment effect. (LLM, conf=0.82)

  cites [362] Matsuzawa, 2020, Renin-angiotensin system inhibitors and the severity of coronavirus disease 2019 in Kanagawa, Japan: a retrospective cohort study, Hypertens. Res. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results > Sub-analyses and Discussion report an exploratory association between ACE inhibitor or ARB use and lower mortality in COVID-19 patients with hypertension, while cautioning that the evidence cannot establish a definite benefit. The paper does not report that these drugs decrease serum IL-6 levels; a search for serum IL-6 found no supporting passage. (LLM, conf=0.86)

  cites [363] Caldeira, 2020, Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers and the risk of COVID-19 infection or severe disease: systematic review and meta-analysis, Int. J. Cardiol. Heart Vasc. sourceExperimental — accuracy not yet measured

In the paper

“Among the elevated inflammatory mediators, the blood IL-6 level is highly correlated with the disease mortality (293, 338) and predicts the need for mechanical ventilation (339).”

What the sources say

• Supported

  In the Results (page not available), IL-6 levels were higher in non-survivors than survivors throughout the clinical course. The reported difference at admission was statistically significant, and higher IL-6 was associated with in-hospital death in univariable analysis. These findings support the claimed association for hospitalized adults with COVID-19. (LLM, conf=0.90)

  cites [293] Zhou, 2020, Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study, Lancet source
• Partly supported

  The paper states in its main text (indexed under Abstract; page unavailable) that a large retrospective cohort study found IL-6 levels correlated with mortality in patients with COVID-19. It does not establish that the correlation was *high*, so the claim overstates the reported strength. The mechanical-ventilation claim is attached to a different citation and is not assessed here. (LLM, conf=0.85)

  cites [338] Liu, 2020, Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?, J. Autoimmun. sourceExperimental — accuracy not yet measured

In the paper

“Furthermore, the ACE1 II genotype is protective against COVID-19 as compared to the ACE1 DD genotype (358), and serum levels of ACE1 are higher in the DD genotype compared with the II genotype (359).”

What the sources say

• Supported

  Table II in the Serum ACE concentrations section reports mean serum ACE concentrations of 494.1 µg/L for the DD genotype and 299.3 µg/L for the II genotype. The Discussion (p. 1343–1346) likewise states that subjects with the deletion polymorphism had higher ACE levels than those with the insertion polymorphism. (LLM, conf=0.95)

  cites [359] Rigat, 1990, An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels, J. Clin. Invest. source

In the paper

“It is triggered by the activation of CAR-T cells that recognize cognate antigens expressed by tumor cells, leading to the release of cytokines and chemokines, including IL-6 in parallel with the release of pro-inflammatory cytokines and chemokines by monocytes and/or macrophages (351, 352).”

What the sources say

• ?Not checked — no full text of the sourcecites [351] June, 2018, CAR T cell immunotherapy for human cancer, Science source
• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [352] Neelapu, 2018, Chimeric antigen receptor T-cell therapy—assessment and management of toxicities, Nat. Rev. Clin. Oncol. source

In the paper

“In addition, dexamethasone reduces the death rate of patients with severe COVID-19 (370).”

What the sources say

• Supported

  The Discussion reports lower 28-day mortality with dexamethasone among hospitalized COVID-19 patients receiving oxygen or invasive mechanical ventilation. These respiratory-support groups substantiate the claim about severe COVID-19; the paper reports no benefit for patients not requiring respiratory support. Page numbers were not supplied. (LLM, conf=0.93)

  cites [370] Group, 2021, Dexamethasone in hospitalized patients with Covid-19—preliminary report, N Engl J Med. source

In the paper

“The AngII–AT1R signaling system plays an important role not only in pneumonia but also in ARDS model mice (345), indicating that lung injury itself activates the AngII–AT1R signaling.”

What the sources say

• Supported

  The Main section reports that acid-induced acute lung injury in mice increased lung AngII levels and reduced ACE2 expression. It also reports that AT1 blockade attenuated injury and concludes that AngII acting through AT1a has a causative role in acute lung failure. Together, these findings support the citing sentence’s inference that lung injury activates AngII–AT1R signaling in the mouse model. (LLM, conf=0.91)

  cites [345] Imai, 2005, Angiotensin-converting enzyme 2 protects from severe acute lung failure, Nature source

In the paper

“The anti-IL-6R antibodies tocilizumab and sarilumab are used to treat RA, Castleman’s disease and CAR-T-induced CRS (71–75, 352, 364) and have promise for treating the severe form of COVID-19 (365–367).”

What the sources say

• ?Not checked — no full text of the sourcecites [71] Choy, 2002, Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial, Arthritis Rheum. source
• Partly supported

  The Study drug and Discussion sections describe MRA as an anti-IL-6R antibody used to treat multicentric Castleman disease, and the study reports improvement in those patients. Our copy does not identify MRA as tocilizumab or address sarilumab, rheumatoid arthritis treatment, or CAR-T-induced CRS, so it supports only the Castleman disease portion of the attributed claim. (LLM, conf=0.88)

  cites [72] Nishimoto, 2005, Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease, Blood sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [73] Maini, 2006, Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate, Arthritis Rheum. source
• ?Not checked — no full text of the sourcecites [74] Genovese, 2008, Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study, Arthritis Rheum. source
• Partly supported

  The introduction identifies tocilizumab as an anti-IL-6 receptor antibody, and the Discussion supports its use in moderate to severe rheumatoid arthritis. The paper does not address sarilumab, Castleman’s disease, or CAR-T-induced cytokine release syndrome. Page numbers are not available in our copy. (LLM, conf=0.88)

  cites [75] Jones, 2010, Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study, Ann. Rheum. Dis. sourceExperimental — accuracy not yet measured
• Partly supported

  The “IL-6 and IL-6R antagonists” section (page unavailable) identifies tocilizumab as an anti-IL-6R antibody used for rheumatoid arthritis and CAR-T-induced CRS. It does not mention sarilumab; for multicentric Castleman disease, it names siltuximab, which it describes as an anti-IL-6 antibody rather than an anti-IL-6R antibody. (LLM, conf=0.90)

  cites [352] Neelapu, 2018, Chimeric antigen receptor T-cell therapy—assessment and management of toxicities, Nat. Rev. Clin. Oncol. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Cytokine-Release Syndrome) report that tocilizumab, an IL-6 receptor–blocking antibody, was used to manage severe cytokine-release syndrome after CAR-T therapy. The cited paper does not support the claims about sarilumab or use for rheumatoid arthritis or Castleman’s disease. (LLM, conf=0.88)

  cites [364] Maude, 2014, Chimeric antigen receptor T cells for sustained remissions in leukemia, N. Engl. J. Med. sourceExperimental — accuracy not yet measured

In the paper

“Other inhibitors against the IL-6–STAT3 signaling pathway are under development (19, 21, 24–26, 76, 374).”

What the sources say

• Supported

  In “Targeting STAT3 for cancer therapy” (page not provided), the review describes several types of STAT3 inhibitors and says new classes of JAK2-targeting inhibitors had been identified for clinical development. It also identifies IL-6–JAK signalling as important in STAT3 activation, supporting the claim that inhibitors of this pathway were under development. (LLM, conf=0.91)

  cites [19] Yu, 2009, STATs in cancer inflammation and immunity: a leading role for STAT3, Nat. Rev. Cancer source
• ?Not checked — no full text of the sourcecites [21] Hunter, 2015, IL-6 as a keystone cytokine in health and disease, Nat. Immunol. source
• Supported

  The Therapeutic strategies section describes JAK inhibitors in clinical trials and several other inhibitors targeting STAT3 activity. Figure 3 places interventions affecting IL-6-family receptor and JAK–STAT signalling in a clinical-development pipeline. The supplied passages do not give page numbers. (LLM, conf=0.93)

  cites [24] Jones, 2018, Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer, Nat. Rev. Immunol. source
• Partly supported

  The Conclusions (section 5; page unavailable) identify direct STAT3 inhibitors and indirect approaches that block IL-6 or JAK2 signaling, and discuss the complexity of clinical development. They do not clearly state that other IL-6–STAT3 inhibitors are currently under development. (LLM, conf=0.78)

  cites [25] Rebe, 2019, STAT3, a master regulator of anti-tumor immune response, Cancer sourceExperimental — accuracy not yet measured
• Supported

  The Future directions section explicitly states that novel inhibitors of the IL-6/JAK/STAT3 pathway, including STAT3-selective agents, are being developed. The STAT3 inhibitors section also describes compounds that have reached clinical trials. (LLM, conf=0.95)

  cites [26] Johnson, 2018, Targeting the IL-6/JAK/STAT3 signalling axis in cancer, Nat. Rev. Clin. Oncol. source

In the paper

“Moreover, the IL-6 Amp is related with various types of cancer, including hematologic malignancies, tumors in lung, and colorectal/intestinal, urinary/bladder/vulvar, breast, stomach and liver cancers (11).”

What the sources say

• ?Not checked — no full text of the sourcecites [11] Atsumi, 2014, Inflammation amplifier, a new paradigm in cancer biology, Cancer Res. source

In the paper

“Furthermore, many cancer-associated genes were identified as regulators or target genes of the IL-6 Amp (11).”

What the sources say

• ?Not checked — no full text of the sourcecites [11] Atsumi, 2014, Inflammation amplifier, a new paradigm in cancer biology, Cancer Res. source

In the paper

“and is present at high amounts in the synovial fluid of rheumatoid arthritis (RA) patients (44, 45)”

What the sources say

• ?Not checked — no full text of the sourcecites [44] Hirano, 1988, Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis, Eur. J. Immunol. source
• ?Not checked — no full text of the sourcecites [45] Houssiau, 1988, Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides, Arthritis Rheum. source

In the paper

“The IL-6 amplifier (IL-6 Amp) is an amplification mechanism for the production of IL-6 and a variety of other cytokines and chemokines through a synergic interaction between STAT3 and nuclear factor-kappa B (NF-κB).”

In the paper

“IL-6 together with TGFβ induces Th17 cells (Fig. 2) (164).”

What the sources say

• ?Not checked — no full text of the sourcecites [164] Veldhoen, 2006, TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells, Immunity source

In the paper

“In addition, IL-6 and sIL-6Rα induce a transition between the early predominantly neutrophilic stage of an infection and the more sustained mononuclear cell influx, contributing to the switch from acute to chronic inflammation (98).”

What the sources say

• ?Not checked — no full text of the sourcecites [98] Hurst, 2001, Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation, Immunity source

In the paper

“However, IL-6 complexed with the soluble form of IL-6Rα (sIL-6Rα) can act on cells expressing only gp130, such as heart muscle cells.”

In the paper

“Instead, hyper-activation of the immune system to the target tissue may be a consequent event that is initiated by local initiators in non-immune target tissue in a manner dependent on genetic and/or environmental factors (1, 47, 48, 50).”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Hirano, 1998, Interleukin 6 and its receptor: ten years later, Int. Rev. Immunol. source
• ?Not checked — no full text of the sourcecites [47] Boyden, 1964, Autoimmunity and inflammation, Nature source
• ?Not checked — no full text of the sourcecites [48] Wilkin, 1990, The primary lesion theory of autoimmunity: a speculative hypothesis, Autoimmunity source

In the paper

“PD-L1, which is a ligand of PD-1, is expressed in tumor microenvironments and tumors in a manner dependent on STAT3.”

In the paper

“On the other hand, IL-6 inhibits the TGFβ-induced generation of Treg cells (166).”

What the sources say

• ?Not checked — no full text of the sourcecites [166] Bettelli, 2006, Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells, Nature source

In the paper

“Taken together with the fact that the development of pristane or mineral oil-induced plasmacytoma and obesity-related hepatocellular carcinoma (HCC), both of which are related to inflammation, are dependent on IL-6 (254, 258), all studies indicate the intimate link between inflammation and tumorigenesis via IL-6–STAT3 signaling.”

In the paper

“Taking the above together with the fact that IL-6 is a growth factor for plasmacytoma and myeloma (28, 37)”

What the sources say

• ?Not checked — no full text of the sourcecites [28] Van Snick, 1990, Interleukin-6: an overview, Annu. Rev. Immunol. source
• ?Not checked — no full text of the sourcecites [37] Kawano, 1988, Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas, Nature source

In the paper

“All evidence indicates that IL-6–STAT3 signaling determines the homeostasis of Th17 cells and Treg cells.”

In the paper

“All evidence supports the idea that the immune system tightly regulates Th17/Treg cell homeostasis through the IL-6–IL-2 axis, and the disturbance of this balance in the presence of TGFβ causes inflammation and autoimmunity (Fig. 2).”

In the paper

“Further, the mice show a similar expression pattern of STAT3-dependent miR-200 family members with that of early stage gastric cancer patients (142).”

What the sources say

• ?Not checked — no full text of the sourcecites [142] Yu, 2018, Clinical utility of a STAT3-regulated miRNA-200 family signature with prognostic potential in early gastric cancer, Clin. Cancer Res. source

In the paper

“Overall, accumulating evidence supports the intimate relationship of IL-6 with inflammation, autoimmunity and cancer (Fig. 2).”

In the paper

“It has not yet been reported whether gp130Y757F/Y757F mice spontaneously develop arthritis as F759 mice do, but AIA, which is also IL-6-dependent, is enhanced in gp130Y757F/Y757F mice in a manner dependent on STAT3 (259).”

What the sources say

• ?Not checked — no full text of the sourcecites [259] Nowell, 2009, Therapeutic targeting of IL-6 trans signaling counteracts STAT3 control of experimental inflammatory arthritis, J. Immunol. source

In the paper

“As described above, the IL-6 Amp is a mechanism by which the regional production of a variety of cytokines and growth factors is augmented through the interaction between NF-κB and STAT3, both of which are activated not only in inflammatory lesions but also in tumor microenvironments and neoplastic tumor cells.”

In the paper

“The interaction between immune cells and non-immune cells further strengthens the IL-6 Amp.”

In the paper

“Consistent with the concept that IL-6 Amp activation in non-immune cells plays a pivotal role in the development of autoimmune diseases, mice devoid of STAT3 or gp130 in non-immune cells like type-1 collagen positive cells are highly resistant to F759 arthritis and EAE (54, 66).”

In the paper

“In line with this notion, there is a correlation between IL-6 and the severity of RA and other inflammatory and autoimmune diseases (3, 260, 261).”

What the sources say

• ?Not checked — no full text of the sourcecites [3] Ishihara, 2002, IL-6 in autoimmune disease and chronic inflammatory proliferative disease, Cytokine Growth Factor Rev. source
• ?Not checked — no full text of the sourcecites [260] de Benedetti, 1991, Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis, Arthritis Rheum. source
• ?Not checked — no full text of the sourcecites [261] Reinisch, 1999, Clinical relevance of serum interleukin-6 in Crohn’s disease: single point measurements, therapy monitoring, and prediction of clinical relapse, Am. J. Gastroenterol. source

In the paper

“Further, a non-conservative SNP in the gp130, Gly148Arg, which has low IL-6 responsiveness, is associated with a decreased risk of myocardial infarction in a hypertensive population (276).”

What the sources say

• ?Not checked — no full text of the sourcecites [276] Benrick, 2008, A non-conservative polymorphism in the IL-6 signal transducer (IL6ST)/gp130 is associated with myocardial infarction in a hypertensive population, Regul. Pept. source

In the paper

“The IL-6 Amp recruits immune cells such as activated T cells into the lesion by chemokines.”

In the paper

“Although the development of F759 arthritis is dependent on Th17 cells, the F759 mutation is required in non-immune cells but not immune cells, clearly indicating that the interaction between non-immune cells and immune cells is crucial for arthritis development in F759 mice (66, 99).”

In the paper

“Accumulated immune cells interact with non-immune cells in inflammatory lesions and tumor microenvironments as well as with tumor cells to further enhance the IL-6 Amp by producing not only IL-6 but also a variety of IL-6 Amp stimulators such as IL-17, TNFα, IL-1 and epiregulin.”

In the paper

“The IL-6 Amp, which is activated not only in non-immune cells such as fibroblasts and endothelial cells but also in grafted organs and tumor cells, acts as a linker between these cells and immune cells by attracting immune cells through the production of a variety of chemokines.”

In the paper

“Age-related changes in senescent cells also act as local initiators.”

In the paper

“Therefore, the local initiation model could be applied not only to chronic inflammatory diseases and autoimmune diseases, but also to age-related diseases and cancer (Fig. 4).”

In the paper

“Persistent local initiator activity, such as chronic infections, with or without genetic factors leads to chronic activation of the IL-6 Amp.”

In the paper

“In this model, NF-κB and STAT3 are activated by a variety of local initiators, including injury, infection, stressors, age-related events in senescent cells and oncogenic mutation in pre-neoplastic cells, leading to the activation of the IL-6 Amp in non-immune cells, such as fibroblasts, epithelial cells, endothelial cells and adipocytes.”

In the paper

“Consistently, IL-6 levels increase with age (296, 297).”

What the sources say

• ?Not checked — no full text of the sourcecites [296] Daynes, 1993, Altered regulation of IL-6 production with normal aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative, J. Immunol. source
• ?Not checked — no full text of the sourcecites [297] Hong, 2007, Interleukin-6 and its receptor in cancer: implications for translational therapeutics, Cancer source

In the paper

“MSLN also promotes pancreatic cancer cell proliferation through autocrine IL-6 trans-signaling (320).”

What the sources say

• ?Not checked — no full text of the sourcecites [320] Bharadwaj, 2011, Mesothelin overexpression promotes autocrine IL-6/sIL-6R trans-signaling to stimulate pancreatic cancer cell proliferation, Carcinogenesis source

In the paper

“The IL-6 Amp at the leading edge could play a critical role in tumor progression.”

In the paper

“Pre-neoplastic cells or cancer cells by themselves act as local initiators much like senescent cells do.”

In the paper

“These findings support the idea that obesity-induced mechanical and/or ER stress and lipid metabolites act as local initiators in the target tissue to trigger chronic activation of the IL-6 Amp.”

In the paper

“For the initial detection of microbes, the immune system utilizes pattern-recognition receptors (PRRs), such as TLRs to activate MyD88-dependent signaling and ultimately activate NF-κB (324).”

What the sources say

• ?Not checked — no full text of the sourcecites [324] Kawai, 2010, The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors, Nat. Immunol. source

In the paper

“Therefore, infection is one trigger of the IL-6 Amp.”

In the paper

“RANTES and MCP-1 secreted by tumor cells and tumor-derived fibroblasts mediate the recruitment of Th17 cells (159).”

What the sources say

• ?Not checked — no full text of the sourcecites [159] Su, 2010, Tumor microenvironments direct the recruitment and expansion of human Th17 cells, J. Immunol. source

In the paper

“The massive cell death commonly observed in cytokine storm, regardless of the inducer type, activates damage-associated molecular pattern (DAMP) receptor-mediated signaling pathways and/or TLR-mediated ones.”

In the paper

“These events further induce pro-inflammatory cytokines including IL-6 through NF-κB activation.”

In the paper

“Furthermore, it has been shown that ARDS and renal dysfunction induced in a sepsis rat model are suppressed by anti-IL-6R antibody through the suppression of NF-κB activation (356).”

What the sources say

• ?Not checked — no full text of the sourcecites [356] Ibrahim, 2020, Tocilizumab attenuates acute lung and kidney injuries and improves survival in a rat model of sepsis via down-regulation of NF-κB/JNK: a possible role of P-glycoprotein, Inflammopharmacology source

In the paper

“ARDS with a cytokine storm occurs in viral infections such as MERS-CoV, influenza virus and sepsis.”

What the sources say

• ?Not checked — no full text of the sourcecites [334] Thompson, 2017, Acute respiratory distress syndrome, N. Engl. J. Med. source

In the paper

“Interestingly, ACE1 gene polymorphisms are involved in the development and severity of ARDS (357).”

What the sources say

• ?Not checked — no full text of the sourcecites [357] Marshall, 2002, Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome, Am. J. Respir. Crit. Care Med. source

In the paper

“Cytokine storm also occurs in CAR-T treatment, which is used to treat leukemia.”

In the paper

“Therefore, NF-κB and STAT3 are the basis of the IL-6 Amp which is the amplification mechanism of IL-6 itself and other pro-inflammatory molecules, such as cytokines, chemokines and growth factors.”

In the paper

“Inflammatory diseases, autoimmune diseases and cancer are induced by complex interactions between non-immune cells and immune cells via the IL-6 Amp.”

In the paper

“Therefore, the expression and/or functions of IL-6 Amp-related molecules could be used to predict diseases initiated by local initiators.”

In the paper

“One of the reasons why IL-6 is a key cytokine in inflammation is that it has a wide range of target cells because of its trans-signaling mechanism.”

In the paper

“For this action, sIL-6Rα is required.”

What the sources say

• ?Not checked — no full text of the sourcecites [96] Rose-John, 2017, The soluble interleukin 6 receptor: advanced therapeutic options in inflammation, Clin. Pharmacol. Ther. source

In the paper

“Since the IL-6 Amp is deeply involved in uncontrolled inflammation, it is critical to elucidate the genetic and environmental factors that destabilize it.”