IL-6 in inflammation, autoimmunity and cancer

Interactions between immune cells and non-immune tissues play critical roles in chronic inflammatory diseases and autoimmune diseases.

“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).”

• cites [3] Ishihara, 2002, IL-6 in autoimmune disease and chronic inflammatory proliferative disease, Cytokine Growth Factor Rev. sourceNot checked — no full text of the source
• cites [41] Hirano, 2010, Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir, Proc. Jpn Acad. Ser. B. Phys. Biol. Sci. sourcePartly 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)

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• cites [49] Matsumoto, 2002, How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease, Nat. Immunol. sourceNot checked — no full text of the source
• cites [50] Marrack, 2001, Autoimmune disease: why and where it occurs, Nat. Med. sourceNot checked — no full text of the source
• cites [51] Hirano, 2002, Revival of the autoantibody model in rheumatoid arthritis, Nat. Immunol. sourceNot checked — no full text of the source

Tissue property-dependent events, microbleeding, neural stimulation, cell senescence and oncogenic mutations in pre-neoplastic cells have been shown to trigger interactions between immune cells and non-immune tissues.

“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.”

• cites [49] Matsumoto, 2002, How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease, Nat. Immunol. sourceNot checked — no full text of the source
• 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. sourceSupported
• cites [53] Leavy, 2011, Autoimmunity: joint damage without antigen, Nat. Rev. Immunol. sourceNot checked — no full text of the source

Interactions between a tumor and its microenvironment through the immune system are critical for tumor development and progression.

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

• cites [2] Balkwill, 2001, Inflammation and cancer: back to Virchow?, Lancet sourceNot checked — no full text of the source
• cites [6] Mantovani, 2008, Cancer-related inflammation, Nature sourceSupported
• cites [9] Grivennikov, 2010, Immunity, inflammation, and cancer, Cell sourceSupported

The IL-6 amplifier plays a key role in inflammatory diseases including cytokine storm syndromes, autoimmune diseases and cancer.

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

• cites [10] Murakami, 2013, Disease-association analysis of an inflammation-related feedback loop, Cell Rep. sourcePartly 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)

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• cites [11] Atsumi, 2014, Inflammation amplifier, a new paradigm in cancer biology, Cancer Res. sourceNot checked — no full text of the source
• cites [15] Hirano, 2020, COVID-19: a new virus, but a familiar receptor and cytokine release syndrome, Immunity sourcePartly 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)

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The IL-6-STAT3 pathway is now considered a major target for the treatment of inflammatory diseases.

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

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

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

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• cites [21] Hunter, 2015, IL-6 as a keystone cytokine in health and disease, Nat. Immunol. sourceNot checked — no full text of the source

F759/F757-dependent negative regulation is mainly dependent on the recruitment of SOCS3.

“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).”

• cites [116] Lehmann, 2003, SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130, J. Biol. Chem. sourcePartly 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)

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

The trans-signaling mode plays crucial roles in chronic inflammation.

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

• cites [33] Murakami, 2019, Pleiotropy and specificity: insights from the interleukin 6 family of cytokines, Immunity sourceCould 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)

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• cites [96] Rose-John, 2017, The soluble interleukin 6 receptor: advanced therapeutic options in inflammation, Clin. Pharmacol. Ther. sourceNot checked — no full text of the source

STAT3-induced miR-21 and miR-181b-1 activate NF-κB, resulting in the induction of IL-6 gene expression.

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

• 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 sourceSupported

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.

“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).”

• cites [33] Murakami, 2019, Pleiotropy and specificity: insights from the interleukin 6 family of cytokines, Immunity sourceCould 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)

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Defective STAT3 activation enhances SHP-2-ERK-MAPK activation pathways, most likely through an impaired STAT3-mediated induction of SOCS3.

“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).”

• 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. sourcePartly 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)

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• 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. sourceSupported

The IL-6-STAT3-Pim kinase axis is involved in the development and cell growth of pancreatic cancer.

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

• cites [128] Block, 2012, IL-6 stimulates STAT3 and Pim-1 kinase in pancreatic cancer cell lines, Pancreas sourcePartly 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)

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• cites [129] Xu, 2016, PIM-1 contributes to the malignancy of pancreatic cancer and displays diagnostic and prognostic value, J. Exp. Clin. Cancer Res. sourcePartly 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)

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These multiple signal transduction pathways intimately regulate cell survival, proliferation, inflammation, immunity, angiogenesis, and tumor development and progression through the expression of several genes.

“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).”

• cites [1] Hirano, 1998, Interleukin 6 and its receptor: ten years later, Int. Rev. Immunol. sourceNot checked — no full text of the source
• cites [19] Yu, 2009, STATs in cancer inflammation and immunity: a leading role for STAT3, Nat. Rev. Cancer sourceSupported
• cites [21] Hunter, 2015, IL-6 as a keystone cytokine in health and disease, Nat. Immunol. sourceNot checked — no full text of the source

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

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

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

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IL-6-induced STAT3 activation is critical for in vivo plasma cell survival and immunoglobulin secretion in humans.

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

• 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. sourceSupported

Serum IL-6 levels in rheumatoid arthritis patients correlate with clinical and laboratory indices of the disease.

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

• cites [234] Madhok, 1993, Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity, Ann. Rheum. Dis. sourcePartly 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)

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Enhancement of IL-6-STAT3 signaling causes IL-17A-dependent autoimmune arthritis in mice.

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

• cites [41] Hirano, 2010, Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir, Proc. Jpn Acad. Ser. B. Phys. Biol. Sci. sourceSupported
• cites [63] Atsumi, 2002, A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis, J. Exp. Med. sourcePartly 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)

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

Myeloid-derived suppressor cell function is dependent on STAT3.

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

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

Chronic inflammation is often accompanied with autoimmune disease and cancer.

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

• cites [2] Balkwill, 2001, Inflammation and cancer: back to Virchow?, Lancet sourceNot checked — no full text of the source
• cites [4] Coussens, 2002, Inflammation and cancer, Nature sourceSupported
• cites [9] Grivennikov, 2010, Immunity, inflammation, and cancer, Cell sourceSupported

Environmental factors, such as infection, stress, obesity, aging and smoking, each of which can induce chronic inflammation, could be a major cause of oncogenesis.

“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).”

• cites [4] Coussens, 2002, Inflammation and cancer, Nature sourcePartly 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)

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• cites [6] Mantovani, 2008, Cancer-related inflammation, Nature sourcePartly 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)

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• cites [9] Grivennikov, 2010, Immunity, inflammation, and cancer, Cell sourcePartly 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)

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Gp130Y757F/Y757F mice show enhanced colitis-associated tumorigenesis in a manner dependent on enhanced activation of STAT3.

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

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

True pathogenic antigens causing the breakdown have not been identified for many autoimmune diseases, including rheumatoid arthritis and other tissue-specific disorders.

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

• cites [229] Inshaw, 2018, Approaches and advances in the genetic causes of autoimmune disease and their implications, Nat. Immunol. sourceCould 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)

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• cites [230] Rothhammer, 2016, Environmental control of autoimmune inflammation in the central nervous system, Curr. Opin. Immunol. sourceCould 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)

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• cites [231] Mathis, 2004, Back to central tolerance, Immunity sourceNot checked — no full text of the source

Several inflammatory and autoimmune diseases, including rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease, show a bias for Th17 cells over Treg cells.

“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).”

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

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.

“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).”

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

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 arthritis development.

“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).”

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

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• 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. sourcePartly 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)

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Loss-of-function mutations of TRAF3, a negative regulator of IL-6-STAT3 signaling, are observed in B-cell lymphoma and multiple myeloma patients.

“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).”

• cites [122] Lin, 2015, The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development, Sci. Signal. sourceSupported
• cites [273] Annunziata, 2007, Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma, Cancer Cell sourceNot checked — no full text of the source
• cites [274] Keats, 2007, Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma, Cancer Cell sourceNot checked — no full text of the source

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.

“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).”

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

Somatic gain-of-function mutations in gp130 that activate gp130-STAT3 signaling lead to inflammatory hepatocellular tumors.

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

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

Amplification of the IL-6-STAT3 axis is augmented by several pathways after the induction of other STAT3 and NF-κB activators during inflammation.

“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).”

• cites [41] Hirano, 2010, Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir, Proc. Jpn Acad. Ser. B. Phys. Biol. Sci. sourceSupported
• cites [66] Ogura, 2008, Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction, Immunity sourcePartly 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)

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There is a correlation between IL-6 and the prognosis of 23 different cancer types.

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

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

STAT3 directly binds to the IL-6 promoter to induce IL-6 gene expression.

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

• cites [82] Yoon, 2010, STAT3 transcriptional factor activated by reactive oxygen species induces IL6 in starvation-induced autophagy of cancer cells, Autophagy sourceSupported
• cites [83] Chang, 2013, The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis, Neoplasia sourceSupported

IL-6R is associated with asthma and atopic dermatitis.

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

• cites [270] Ferreira, 2011, Identification of IL6R and chromosome 11q13.5 as risk loci for asthma, Lancet sourcePartly 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)

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• cites [271] Esparza-Gordillo, 2013, A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis, J. Allergy Clin. Immunol. sourceNot checked — no full text of the source

Mice devoid of STAT3 or gp130 in non-immune cells like type-1 collagen positive cells are highly resistant to F759 arthritis and EAE.

“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).”

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

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

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NF-κB and STAT3 play crucial roles in cancer development and progression.

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

• cites [19] Yu, 2009, STATs in cancer inflammation and immunity: a leading role for STAT3, Nat. Rev. Cancer sourceSupported
• cites [25] Rebe, 2019, STAT3, a master regulator of anti-tumor immune response, Cancer sourcePartly 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)

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

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.

“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).”

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

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Produced IL-6 further induces Th17 cell differentiation through STAT3 in the presence of TGFβ, IL-1β and IL-23, which are rich in inflammatory lesions and tumor microenvironments.

“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).”

• cites [164] Veldhoen, 2006, TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells, Immunity sourceNot checked — no full text of the source
• cites [166] Bettelli, 2006, Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells, Nature sourceNot checked — no full text of the source
• cites [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. sourceNot checked — no full text of the source
• cites [170] Wilson, 2007, Development, cytokine profile and function of human interleukin 17-producing helper T cells, Nat. Immunol. sourceNot checked — no full text of the source
• cites [171] Ghoreschi, 2010, Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling, Nature sourcePartly 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)

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F759 arthritis development is dependent on Th17 cells.

“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).”

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

  Experimental — accuracy not yet measured
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

NF-κB increases IL-6 levels by inhibiting let-7 expression.

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

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

STAT3 activates NF-κB through the direct induction of miR-21 and miR-181b-1, leading to IL-6 gene expression.

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

• 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 sourceSupported

GWAS, meta-analysis, exome analysis and SNP mapping have associated IL-6, IL-6R and gp130 with inflammatory diseases such as RA and coronary artery disease.

“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).”

• cites [263] Dar, 2017, Interleukin-6-174G > C (rs1800795) polymorphism distribution and its association with rheumatoid arthritis: a case-control study and meta-analysis, Autoimmunity sourceNot checked — no full text of the source
• cites [264] Hou, 2015, Association of interleukin-6 gene polymorphism with coronary artery disease: an updated systematic review and cumulative meta-analysis, Inflamm. Res. sourceNot checked — no full text of the source
• 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 sourcePartly 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)

  Experimental — accuracy not yet measured
• 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. sourcePartly 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)

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

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

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

  Experimental — accuracy not yet measured

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.

“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).”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

Local initiators such as microbleeding induce the accumulation of T cells in the joints through CCL20 production.

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

• 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. sourceSupported

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

“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).”

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

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.

“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).”

• cites [7] Kuilman, 2008, Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network, Cell sourcePartly 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)

  Experimental — accuracy not yet measured

Even in T1D in which tissue-specific T cells are involved, local initiators originating from senescent beta cells play critical roles.

“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.”

• cites [299] Bluestone, 2010, Genetics, pathogenesis and clinical interventions in type 1 diabetes, Nature sourceSupported
• cites [300] Wållberg, 2013, Immune mechanisms in type 1 diabetes, Trends Immunol. sourceNot checked — no full text of the source
• cites [301] Christoffersson, 2016, Recent advances in understanding type 1 diabetes, F1000Res. sourceSupported

Even T-cell-dependent tissue-specific autoimmune diseases do not necessarily require antigen-specific T cells.

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

• 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. sourceSupported

The gateway reflex 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.

“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).”

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

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

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

  Experimental — accuracy not yet measured

Pain sensation induces a relapse of EAE by activating the IL-6 Amp through another sensory-sympathetic neural network.

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

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

Target molecules of the IL-6 Amp include EGFR, c-Myc, Pim1, VEGFα, hypoxia-inducible factor 1-alpha, MMPs and many pro-inflammatory cytokines and growth factors involved in cell survival, proliferation, angiogenesis and metastasis.

“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).”

• cites [10] Murakami, 2013, Disease-association analysis of an inflammation-related feedback loop, Cell Rep. sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [11] Atsumi, 2014, Inflammation amplifier, a new paradigm in cancer biology, Cancer Res. sourceNot checked — no full text of the source

S1P activates STAT3 through its G protein-coupled receptor, S1P receptor-1.

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

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

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.

“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.”

• 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. sourceSupported

The severity of COVID-19 is associated with an increased level of inflammatory cytokines, such as IL-6, GM-CSF and TNFα.

“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).”

• cites [333] Huang, 2020, Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Lancet sourcePartly 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)

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

  Experimental — accuracy not yet measured

HER2 expression in breast cancer activates an IL-6 autocrine signaling loop to activate STAT3, which is critical for tumorigenesis.

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

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

Severe COVID-19 is a cytokine storm syndrome.

“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).”

• cites [12] Mehta, 2020, COVID-19: consider cytokine storm syndromes and immunosuppression, Lancet sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [13] Mahmudpour, 2020, COVID-19 cytokine storm: the anger of inflammation, Cytokine sourceSupported
• cites [14] Hu, 2021, The cytokine storm and COVID-19, J. Med. Virol. sourceNot checked — no full text of the source
• cites [15] Hirano, 2020, COVID-19: a new virus, but a familiar receptor and cytokine release syndrome, Immunity sourceSupported
• cites [16] García, 2020, Immune response, inflammation, and the clinical spectrum of COVID-19, Front. Immunol. sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [17] Vabret, 2020, Immunology of COVID-19: current state of the science, Immunity sourceSupported
• cites [336] Mangalmurti, 2020, Cytokine storms: understanding COVID-19, Immunity sourcePartly 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)

  Experimental — accuracy not yet measured

Activated mutant EGFR in lung cancer induces IL-6 gene expression to activate constitutive IL-6-STAT3 signaling in a paracrine and autocrine manner.

“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).”

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

Mutated K-RAS activates NF-κB in a mouse model of lung cancer.

“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).”

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

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.

“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).”

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

This process is critically involved in colitis-associated cancer.

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

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

MSLN confers pancreatic cancer cell resistance to TNFα-induced apoptosis through NF-κB activation and the enhanced expression of IL-6.

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

• 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 sourceSupported

TLRs such as TLR2, TLR4, TLR7 and TLR9 activate STAT3.

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

• cites [206] Kortylewski, 2009, Toll-like receptor 9 activation of signal transducer and activator of transcription 3 constrains its agonist-based immunotherapy, Cancer Res. sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [325] Yu, 2014, Revisiting STAT3 signalling in cancer: new and unexpected biological functions, Nat. Rev. Cancer sourceNot checked — no full text of the source

BRAFE600 induces IL-6 and IL-1, a NF-κB activator, through C/EBPβ.

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

• cites [7] Kuilman, 2008, Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network, Cell sourcePartly 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)

  Experimental — accuracy not yet measured

Blood IL-6 level predicts the need for mechanical ventilation in COVID-19.

“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).”

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

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.

“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).”

• cites [12] Mehta, 2020, COVID-19: consider cytokine storm syndromes and immunosuppression, Lancet sourcePartly 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)

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

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

  Experimental — accuracy not yet measured

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

“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).”

• cites [355] Imai, 2008, Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury, Cell sourcePartly 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)

  Experimental — accuracy not yet measured

The anti-IL-6R antibody tocilizumab is effective at treating patients with CAR-T-induced cytokine release syndrome.

“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).”

• cites [352] Neelapu, 2018, Chimeric antigen receptor T-cell therapy—assessment and management of toxicities, Nat. Rev. Clin. Oncol. sourceSupported
• cites [364] Maude, 2014, Chimeric antigen receptor T cells for sustained remissions in leukemia, N. Engl. J. Med. sourceSupported

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.

“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).”

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

Aging, obesity and inflammation-related diseases such as diabetes and cardiovascular diseases are risk factors for the severity of COVID-19.

“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).”

• 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 sourcePartly 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)

  Experimental — accuracy not yet measured
• 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 sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [372] Guo, 2020, Diabetes is a risk factor for the progression and prognosis of COVID-19, Diabetes Metab. Res. Rev. sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [373] Clerkin, 2020, COVID-19 and cardiovascular disease, Circulation sourceNot checked — no full text of the source

IL-6 and TNFα serum levels are significant predictors of COVID-19 disease severity and death.

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

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

SARS-CoV-1 and MERS-CoV activate NF-κB in a manner dependent on MyD88 through PRRs, such as RIG-I and MDA5, leading to the activation of pro-inflammatory cytokines including IL-6, TNFα, IL-8 and CCL2.

“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).”

• cites [335] de Wit, 2016, SARS and MERS: recent insights into emerging coronaviruses, Nat. Rev. Microbiol. sourcePartly 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)

  Experimental — accuracy not yet measured

The AngII-AT1R axis activates the NF-κB pathway through various growth factors and pro-inflammatory cytokines.

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

• cites [347] Brasier, 2002, Vascular inflammation and the renin-angiotensin system, Arterioscler. Thromb. Vasc. Biol. sourceNot checked — no full text of the source
• cites [348] Hunyady, 2006, Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II, Mol. Endocrinol. sourcePartly 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)

  Experimental — accuracy not yet measured

IL-1 and IL-6 are involved in the lethal cytokine storm sometimes seen in CAR-T treatment.

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

• cites [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. sourceNot checked — no full text of the source
• cites [354] Giavridis, 2018, CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade, Nat. Med. sourceSupported

SARS-CoV-2 uses angiotensin-converting enzyme 2 as a receptor.

“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).”

• cites [342] Zhou, 2020, A pneumonia outbreak associated with a new coronavirus of probable bat origin, Nature sourceSupported
• cites [343] Hoffmann, 2020, SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Cell sourceSupported

The ACE1 II genotype is protective against COVID-19 as compared to the ACE1 DD genotype.

“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).”

• cites [358] Yamamoto, 2020, SARS-CoV-2 infections and COVID-19 mortalities strongly correlate with ACE1 I/D genotype, Gene sourcePartly 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)

  Experimental — accuracy not yet measured

AngII-AT1R axis inhibitors may be beneficial for COVID-19 patients to decrease serum IL-6 levels.

“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).”

• cites [360] Meng, 2020, Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension, Emerg. Microbes Infect. sourcePartly 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)

  Experimental — accuracy not yet measured
• 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. sourcePartly 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)

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

  Experimental — accuracy not yet measured
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

Blood IL-6 level is highly correlated with COVID-19 disease mortality.

“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).”

• 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 sourceSupported
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

Serum levels of ACE1 are higher in the DD genotype compared with the II genotype.

“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).”

• 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. sourceSupported

CAR-T cytokine storm 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.

“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).”

• cites [351] June, 2018, CAR T cell immunotherapy for human cancer, Science sourceNot checked — no full text of the source
• cites [352] Neelapu, 2018, Chimeric antigen receptor T-cell therapy—assessment and management of toxicities, Nat. Rev. Clin. Oncol. sourceSupported

Dexamethasone reduces the death rate of patients with severe COVID-19.

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

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

Lung injury itself activates the AngII-AT1R signaling.

“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.”

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

The anti-IL-6R antibodies tocilizumab and sarilumab are used to treat RA, Castleman's disease and CAR-T-induced CRS.

“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).”

• cites [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. sourceNot checked — no full text of the source
• cites [72] Nishimoto, 2005, Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease, Blood sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [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. sourceNot checked — no full text of the source
• cites [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. sourceNot checked — no full text of the source
• 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. sourcePartly 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)

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

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

  Experimental — accuracy not yet measured

Other inhibitors against the IL-6-STAT3 signaling pathway are under development.

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

• cites [19] Yu, 2009, STATs in cancer inflammation and immunity: a leading role for STAT3, Nat. Rev. Cancer sourceSupported
• cites [21] Hunter, 2015, IL-6 as a keystone cytokine in health and disease, Nat. Immunol. sourceNot checked — no full text of the source
• cites [24] Jones, 2018, Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer, Nat. Rev. Immunol. sourceSupported
• cites [25] Rebe, 2019, STAT3, a master regulator of anti-tumor immune response, Cancer sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [26] Johnson, 2018, Targeting the IL-6/JAK/STAT3 signalling axis in cancer, Nat. Rev. Clin. Oncol. sourceSupported

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.

“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).”

• cites [11] Atsumi, 2014, Inflammation amplifier, a new paradigm in cancer biology, Cancer Res. sourceNot checked — no full text of the source

Many cancer-associated genes were identified as regulators or target genes of the IL-6 Amp.

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

• cites [11] Atsumi, 2014, Inflammation amplifier, a new paradigm in cancer biology, Cancer Res. sourceNot checked — no full text of the source

IL-6 is present at high amounts in the synovial fluid of rheumatoid arthritis patients.

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

• cites [44] Hirano, 1988, Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis, Eur. J. Immunol. sourceNot checked — no full text of the source
• cites [45] Houssiau, 1988, Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides, Arthritis Rheum. sourceNot checked — no full text of the source

The IL-6 amplifier 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 NF-κB.

“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).”

IL-6 together with TGFβ induces Th17 cells.

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

• cites [164] Veldhoen, 2006, TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells, Immunity sourceNot checked — no full text of the source

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.

“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).”

• cites [98] Hurst, 2001, Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation, Immunity sourceNot checked — no full text of the source

IL-6 complexed with the soluble form of IL-6Rα can act on cells expressing only gp130, such as heart muscle cells.

“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.”

Hyper-activation of the immune system to the target tissue may be a consequent event initiated by local initiators in non-immune target tissue in a manner dependent on genetic and/or environmental factors.

“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).”

• cites [1] Hirano, 1998, Interleukin 6 and its receptor: ten years later, Int. Rev. Immunol. sourceNot checked — no full text of the source
• cites [47] Boyden, 1964, Autoimmunity and inflammation, Nature sourceNot checked — no full text of the source
• cites [48] Wilkin, 1990, The primary lesion theory of autoimmunity: a speculative hypothesis, Autoimmunity sourceNot checked — no full text of the source

PD-L1 is expressed in tumor microenvironments and tumors in a manner dependent on STAT3.

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

IL-6 inhibits the TGFβ-induced generation of Treg cells.

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

• cites [166] Bettelli, 2006, Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells, Nature sourceNot checked — no full text of the source

All studies indicate an intimate link between inflammation and tumorigenesis via IL-6-STAT3 signaling.

“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.”

IL-6 is a growth factor for plasmacytoma and myeloma.

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

• cites [28] Van Snick, 1990, Interleukin-6: an overview, Annu. Rev. Immunol. sourceNot checked — no full text of the source
• cites [37] Kawano, 1988, Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas, Nature sourceNot checked — no full text of the source

IL-6-STAT3 signaling determines the homeostasis of Th17 cells and Treg cells.

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

Disturbance of the IL-6-IL-2 axis balance in the presence of TGFβ causes inflammation and autoimmunity.

“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).”

gp130Y757F/Y757F mice show a similar expression pattern of STAT3-dependent miR-200 family members to that of early stage gastric cancer patients.

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

• cites [142] Yu, 2018, Clinical utility of a STAT3-regulated miRNA-200 family signature with prognostic potential in early gastric cancer, Clin. Cancer Res. sourceNot checked — no full text of the source

Overall, accumulating evidence supports the intimate relationship of IL-6 with inflammation, autoimmunity and cancer.

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

AIA, which is IL-6-dependent, is enhanced in gp130Y757F/Y757F mice in a manner dependent on STAT3.

“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).”

• cites [259] Nowell, 2009, Therapeutic targeting of IL-6 trans signaling counteracts STAT3 control of experimental inflammatory arthritis, J. Immunol. sourceNot checked — no full text of the source

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 in inflammatory lesions, tumor microenvironments and neoplastic tumor cells.

“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.”

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

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

IL-6 Amp activation in non-immune cells plays a pivotal role in the development of autoimmune diseases.

“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).”

There is a correlation between IL-6 and the severity of RA and other inflammatory and autoimmune diseases.

“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).”

• cites [3] Ishihara, 2002, IL-6 in autoimmune disease and chronic inflammatory proliferative disease, Cytokine Growth Factor Rev. sourceNot checked — no full text of the source
• cites [260] de Benedetti, 1991, Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis, Arthritis Rheum. sourceNot checked — no full text of the source
• cites [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. sourceNot checked — no full text of the source

A non-conservative SNP in gp130, Gly148Arg, which has low IL-6 responsiveness, is associated with a decreased risk of myocardial infarction in a hypertensive population.

“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).”

• cites [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. sourceNot checked — no full text of the source

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

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

The interaction between non-immune cells and immune cells is crucial for arthritis development in F759 mice.

“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).”

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 IL-6 and other IL-6 Amp stimulators such as IL-17, TNFα, IL-1 and epiregulin.

“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.”

The IL-6 Amp, activated in non-immune cells such as fibroblasts and endothelial cells, grafted organs and tumor cells, acts as a linker between these cells and immune cells by attracting immune cells through the production of chemokines.

“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.”

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

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

The local initiation model could be applied not only to chronic inflammatory diseases and autoimmune diseases, but also to age-related diseases and cancer.

“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).”

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

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

In the local initiation 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 activation of the IL-6 Amp in non-immune cells such as fibroblasts, epithelial cells, endothelial cells and adipocytes.

“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.”

• AssumptionThe authors state this as an assumption: The same cause can induce both RA and IL-6 expression.

IL-6 levels increase with age.

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

• cites [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. sourceNot checked — no full text of the source
• cites [297] Hong, 2007, Interleukin-6 and its receptor in cancer: implications for translational therapeutics, Cancer sourceNot checked — no full text of the source

MSLN promotes pancreatic cancer cell proliferation through autocrine IL-6 trans-signaling.

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

• cites [320] Bharadwaj, 2011, Mesothelin overexpression promotes autocrine IL-6/sIL-6R trans-signaling to stimulate pancreatic cancer cell proliferation, Carcinogenesis sourceNot checked — no full text of the source

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

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

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

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

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.

“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.”

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

“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).”

• cites [324] Kawai, 2010, The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors, Nat. Immunol. sourceNot checked — no full text of the source

Infection is one trigger of the IL-6 Amp.

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

RANTES and MCP-1 secreted by tumor cells and tumor-derived fibroblasts mediate the recruitment of Th17 cells.

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

• cites [159] Su, 2010, Tumor microenvironments direct the recruitment and expansion of human Th17 cells, J. Immunol. sourceNot checked — no full text of the source

Massive cell death commonly observed in cytokine storm, regardless of the inducer type, activates damage-associated molecular pattern receptor-mediated signaling pathways and/or TLR-mediated ones.

“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.”

Massive cell death in cytokine storm further induces pro-inflammatory cytokines including IL-6 through NF-κB activation.

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

ARDS and renal dysfunction induced in a sepsis rat model are suppressed by anti-IL-6R antibody through the suppression of NF-κB activation.

“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).”

• cites [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 sourceNot checked — no full text of the source

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

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

• cites [334] Thompson, 2017, Acute respiratory distress syndrome, N. Engl. J. Med. sourceNot checked — no full text of the source

ACE1 gene polymorphisms are involved in the development and severity of ARDS.

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

• cites [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. sourceNot checked — no full text of the source

Cytokine storm also occurs in CAR-T treatment.

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

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.

“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.”

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

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

The expression and/or functions of IL-6 Amp-related molecules could be used to predict diseases initiated by local initiators.

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

IL-6 is a key cytokine in inflammation because it has a wide range of target cells because of its trans-signaling mechanism.

“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.”

For IL-6 action on non-immune cells, sIL-6Rα is required.

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

• cites [96] Rose-John, 2017, The soluble interleukin 6 receptor: advanced therapeutic options in inflammation, Clin. Pharmacol. Ther. sourceNot checked — no full text of the source

The IL-6 Amp is deeply involved in uncontrolled inflammation.

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