T H 17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity
Open accessAbstract
Ongoing classic IL-6 receptor signaling is required to maintain the T H 17 program, acting upstream of IL-23 to sustain RORγt expression.
AI snapshot
Written from the paper’s full text.
TL;DR
Ongoing classic IL-6 receptor signaling, not IL-6 trans-signaling, is required for maintenance of mouse Th17 cells and their pathogenic function in colitis. IL-6Rα-deficient Th17 cells rapidly lose Th17 transcriptional identity and fail to induce disease, even when co-transferred with wild-type Th17 cells.
Key findings
- In CD4+CD45RBHi transfer colitis, Il6ra−/− naïve CD4+ T cells failed to induce weight loss or significant colonic inflammation 8 weeks after transfer, whereas WT cells did; IL-17A+ and IL-17A+IFN-γ+ cells were significantly reduced in the colonic lamina propria and mesenteric lymph node, while IFN-γ+ relative percentages were unchanged or increased but their numbers were not increased.
- In Th17 transfer colitis, Il6ra−/− Th17 cells induced significantly less pathology at 4 weeks; recovered colonic lamina propria cells showed significant loss of IL-17A+ and IL-17A+IFN-γ+ cells and increased IFN-γ+ percentage, with no difference in Foxp3+ cells. Co-transfer with WT Th17 cells induced colitis but did not rescue phenotype loss, which occurred as early as 2 weeks after transfer.
- Classic signaling was favored in the colon: colon explant cultures showed IL-6 in molar excess relative to sIL-6Rα in all groups, while systemic sIL-6Rα was in excess of both IL-6 and sgp130. WT and Il6ra−/− Th17 cells repopulated the colon equivalently and showed no proliferation defect; nearly 70% of colonic lamina propria T cells from Il6ra−/− Th17 recipients were BrdU+ 4 weeks after transfer.
- RNA-seq of co-transferred colonic lamina propria cells showed Il6ra−/− cells were enriched for Th1-related genes (Ifng, Tbx21, Il12rb2) and lost Th17-related genes (Il17a, Il17f, Il21, Il22, Il23r, Rorc, Ccr6). Enforced RORγt expression in Il6ra−/− Th17 cells increased retention of IL-17A and Th17 genes but did not completely prevent IFN-γ+ transdifferentiation.
Methods
- Two established mouse T cell transfer colitis models were used: CD4+CD45RBHi naïve T cell transfer into Rag1−/− mice and IL-17F Thy1.1+ Th17 transfer into Rag1−/− or Il6−/−.Rag1−/− mice, including co-transfer of congenically marked WT and Il6ra−/− Th17 cells and retroviral RORγt transduction.
- Analyses included flow cytometry for cytokine phenotype, pSTAT3/pSTAT1, apoptosis, and BrdU/Ki67; Milliplex measurement of IL-6, sIL-6Rα, and sgp130 in serum and colon explant cultures; RNA-seq with DESeq2, fgsea, and GSEA; and blinded histopathological scoring.
- Statistical significance used nonparametric two-tailed Mann-Whitney or Kruskal-Wallis tests for pathology data and unpaired two-tailed Student’s t-test or one-way ANOVA for other data, with P ≤ 0.05 considered significant.
Limitations
- Stated: experiments were not blinded to investigators, except histopathological samples were blinded prior to scoring; group sizes were the minimum required to detect statistically significant differences based on previous experience. The paper also states that several mechanisms require further study, including the developmental shift in STAT activation by the IL-6 receptor, regulation of IL-6Rα/gp130 expression, why IL-21 cannot compensate, and whether classic-signaling dominance is common to other barrier tissues.
- Evident: all findings are from mouse colitis models and mouse T cells in vitro, with no human validation; the study does not establish whether the same requirement for ongoing classic IL-6 signaling applies to human Th17 cells or to non-intestinal tissues.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
28 of 42 cited sources checked · 14 supported · 1 flagged · accuracy not yet measured
- Premisecitation
Th17 cells show substantially greater plasticity than Th1 and Th2 cells.
“In contrast to Th1 and Th2 cells, Th17 cells show substantially greater plasticity (19, 23, 65).”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [19] Lee YK, Late developmental plasticity in the T helper 17 lineage. Immunity. 30, 92– 107 (2009). 19119024 PMC3607320 source
The Results section (‘TGF-β Is Required for Maintenance of IL-17 Expression by Th17 Cells’; page unavailable) says Th17 cells appear more plastic than Th1 cells in late-stage cytokine expression. The copy does not make the same plasticity comparison with Th2 cells; searching for ‘Th2’ found discussion of its differentiation factors and cytokines, not that comparison. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [23] Hirota K, Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol. 12, 255– 263 (2011). 21278737 PMC3040235 source
The Introduction (page unavailable) says Th17 cells display considerable plasticity, and the Discussion (page unavailable) describes distinct patterns of plasticity under different inflammatory conditions. The paper does not establish that Th17 cells are substantially more plastic than both Th1 and Th2 cells. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [65] Murphy KM, Stockinger B, Effector T cell plasticity: flexibility in the face of changing circumstances. Nat Immunol. 11, 674– 680 (2010). 20644573 PMC3249647 source
In “Circuit rules” (page unavailable), the paper suggests that Th17 cells may be less stable than Th1 and Th2 cells, and it describes Th17-to-Th1 conversion. That supports a relative-plasticity comparison, but the paper frames it as a possibility rather than establishing the unqualified claim that Th17 cells show substantially greater plasticity. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Premisecitation
Th1-like cells derive from Th17 precursors contingent on intact IL-23-induced STAT4 activation and T-bet expression.
“Th1-like cells, which derive from Th17 precursors contingent on intact IL-23-induced STAT4 activation and T-bet expression”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [73] Harbour SN, Maynard CL, Zindl CL, Schoeb TR, Weaver CT, Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc. Natl. Acad. Sci. U.S.A 112, 7061– 7066 (2015). 26038559 PMC4460486 source
The Significance section (page unavailable) reports that Th1-like cells arise from Th17 precursors, that T-bet is critical, and that IL-23-driven STAT4 signaling is a major contributor. But it describes the transition as only partially dependent on STAT4: IFN-γ-producing cells remained when STAT4 was absent. Requiring intact STAT4 activation overstates that finding. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
Polymorphisms in the IL6RA gene are associated with susceptibility to both RA and IBD.
“An association between polymorphisms in the IL6RA gene and susceptibility to both RA and IBD have been found (77, 78).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [77] Eyre S, High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet. 44, 1336– 1340 (2012). 23143596 PMC3605761 source
The passage labeled Abstract (page not supplied) identifies IL6R as a rheumatoid arthritis susceptibility locus and reports an association for an IL6R-linked SNP. It does not report an association between IL6R polymorphisms and IBD susceptibility; searches for IBD, Crohn disease, and ulcerative colitis did not find one. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [78] Parisinos CA, Variation in interleukin 6 receptor gene associates with risk of Crohn’s disease and ulcerative colitis. YGAST, 1– 17 (2018). PMC6083435 29775600 source
- Premisecitation
IL-17A- and IL-22-producing Th17 cells appear to be protective rather than pathogenic in the intestines.
“Given that IL-17A- and IL-22-producing Th17 cells appear to be protective rather than pathogenic in the intestines (84)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [84] O’Connor W, A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol. 10, 603– 609 (2009). 19448631 PMC2709990 source
The Results ('IL-17A modulates T cell–driven colitis'; page unavailable) show that IL-17A delayed disease onset in a mouse T-cell-transfer model, supporting a protective role in that setting. The paper does not establish that IL-22-producing Th17 cells are protective; the Discussion reports that IL-22 was not responsible for the accelerated disease seen without IL-17A. The claim also extends a model-specific finding to the intestines generally. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
Th1-like cells were critical for colitis development.
“were critical for colitis development (73).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [73] Harbour SN, Maynard CL, Zindl CL, Schoeb TR, Weaver CT, Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc. Natl. Acad. Sci. U.S.A 112, 7061– 7066 (2015). 26038559 PMC4460486 source
- Premisecitation
In systemic Th17-related autoimmune diseases (RA, JIA, systemic sclerosis), treatment with biologics that inhibit IL-6 is an effective or promising therapy.
“In systemic Th17-related autoimmune diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, and systemic sclerosis, treatment with biologics that inhibit IL-6 is an effective or promising therapy (80–82).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [80] Emery P, IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 67, 1516– 1523 (2008). 18625622 PMC3811149 source
- cites [81] Khanna D, Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate). Ann Rheum Dis. 77, 212– 220 (2018). 29066464 PMC5867414 source
- cites [82] Yokota S, Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 371, 998– 1006 (2008). 18358927 source
- Findingown data
IL-6Rα-deficient Th17 cells rapidly lost their Th17 phenotype.
“IL-6Rα–deficient Th17 cells rapidly lost their Th17 phenotype and did not cause disease in two models of colitis.”
Quote in the paperSubstantial claim - Findingown data
Naïve CD4+ T cells deficient in IL-6Rα failed to induce weight loss or significant colonic inflammation in the CD4+ CD45RBHi T cell transfer colitis model.
“the transfer of Il6ra−/− CD4+ cells failed to induce weight loss or significant colonic inflammation.”
Quote in the paperSubstantial claim - Findingown data
Il6ra−/− CD4+ T cells could not produce IL-17A in response to TGF-β + IL-6 under Th17 polarizing conditions.
“under Th17 polarizing conditions, Il6ra−/− CD4+ T cells could not produce IL-17A in response to TGF-β + IL-6”
Quote in the paperSubstantial claim - Findingown data
Absence of IL-6 led to a reduction in the percentage and number of IL-17A+ CD4+ cells recovered from the CLP of colitic mice.
“the absence of IL-6 led to a reduction in the percentage and number of IL-17A+ CD4+ cells recovered from the CLP of colitic mice”
Quote in the paperSubstantial claim - Findingown data
Loss of the Th17 phenotype by Il6ra−/− cells occurred as early as 2 weeks post transfer.
“loss of the Th17 phenotype by Il6ra−/− cells occurred as early as 2 weeks post transfer”
Quote in the paperSubstantial claim - Findingown data
IL-6 signaling is required for maintenance of mouse Th17 cells.
“IL-6 signaling is required for both induction and maintenance of mouse Th17 cells”
Quote in the paperSubstantial claim - Findingown data
Th17 cells from Il6ra−/− mice induced significantly less pathology than WT Th17 cells in Rag1−/− recipients.
“Th17 cells from Il6ra−/− mice induced significantly less pathology”
Quote in the paperSubstantial claim - Findingown data
Il6ra−/− Th17 cells failed to retain their Th17 identity regardless of whether they were transferred individually or with WT cells.
“regardless of whether they were transferred individually or with WT cells, Il6ra−/− Th17 cells failed to retain their Th17 identity”
Quote in the paperSubstantial claim - Findingown data
The lack of IL-6-induced Th17 differentiation in Il6ra−/− CD4+ T cells was restored by recombinant IL-6-sIL-6Ra fusion protein (HDS), which acts exclusively via IL-6 trans-signaling.
“this lack of IL-6–induced Th17 differentiation was restored by using a recombinant IL-6-sIL–6Ra fusion protein (Hyper-DS-sIL-6R; HDS), which acts exclusively via IL-6 trans-signaling”
Quote in the paperSubstantial claim - Findingown data
Il6ra−/− Th17 cells transfected with RORγt had a much greater propensity to retain their Th17 phenotype even in the absence of classical IL-6 signaling.
“Il6ra−/− Th17 cells transfected with RORγt (Il6ra−/− pMIG-RORγt) had a much greater propensity to retain their Th17 phenotype even in the absence of classical IL-6 signaling.”
Quote in the paperSubstantial claim - Findingown data
Only WT CD4+ T cells were responsive to classic IL-6 signaling ex vivo.
“In contrast, only WT CD4+ T cells were responsive to classic IL-6 signaling ex vivo.”
Quote in the paperSubstantial claim - Findingown data
RORγt-transfected Il6ra−/− Th17 cells had a significant increase in expression of genes of the Th17 program compared to empty-vector Il6ra−/− Th17 cells, including Il17a, Rorc, Il17f and Il23r.
“RORγt-transfected Il6ra−/− Th17 cells had a significant increase in expression of genes of the Th17 program compared to empty-vector Il6ra−/− Th17 cells, including Il17a, Rorc, Il17f and Il23r”
Quote in the paperSubstantial claim - Findingown data
Signature Th17 related genes retained in WT but not Il6ra−/− T cells ex vivo included Il17a, Il17f, Il21, Il22, Il23r, Rorc and Ccr6.
“Signature Th17 related genes that were retained in WT but not Il6ra−/− T cells ex vivo included Il17a, Il17f, Il21, Il22, Il23r, Rorc and Ccr6”
Quote in the paperSubstantial claim - Findingown data
IL-6Rα-deficient Th17 cells did not cause disease in two models of colitis.
“IL-6Rα–deficient Th17 cells rapidly lost their Th17 phenotype and did not cause disease in two models of colitis.”
Quote in the paperSubstantial claim - Findingnone given
The stoichiometry of IL-6-IL-6Rα was comparable in both the homeostatic and inflamed intestines.
“Interestingly, the stoichiometry of IL-6–IL-6Rα was comparable in both the homeostatic and inflamed intestines”
Quote in the paperSubstantial claim - Findingown data
Ongoing IL-6 signaling is required for Th17 maintenance.
“Our finding that ongoing IL-6 signaling is required for Th17 maintenance”
Quote in the paperSubstantial claim - Findingreasoning
IL-6Rα-deficient Th17 cells failed to cause colitis in vivo.
“yet failed to cause colitis in vivo.”
Quote in the paperSubstantial claim - Findingnone given
IL-6 trans-signaling was fully sufficient to differentiate Th17 cells in vitro.
“Although IL-6 trans-signaling was fully sufficient to differentiate Th17 cells in vitro”
Quote in the paperNot a substantial claim - Findingown data
IL-6Rα-deficient Th17 cells more readily transitioned to IFN-γ-producing Th1 cells in vitro.
“IL-6Rα-deficient Th17 cells more readily transitioned to IFN-γ–producing Th1 cells in vitro”
Quote in the paperSubstantial claim - Interpretationreasoning
Classic IL-6 signaling proved necessary for Th17 maintenance in the uninflamed and inflamed intestines.
“Importantly, although Th17 cells were fully competent to receive IL-6 trans-signaling, classic IL-6 signaling proved necessary for Th17 maintenance in the uninflamed and inflamed intestines.”
Quote in the paperSubstantial claim - Interpretationown data
There was no difference in the proliferative capacity of Il6ra−/− Th17 cells, whether transferred individually or co-transferred with WT Th17 cells.
“From this we inferred that there was no difference in the proliferative capacity of Il6ra−/− Th17 cells, whether transferred individually or co-transferred with WT Th17 cells.”
Quote in the paperSubstantial claim - Interpretationown data
Continued classic IL-6 receptor signaling, rather than IL-6 trans-signaling, is required to maintain the pathogenic phenotype of Th17 cells in vivo.
“Together, these results suggest that continued classic IL-6 receptor signaling, rather than IL-6 trans-signaling is required to maintain the pathogenic phenotype of Th17 cells in vivo”
Quote in the paperSubstantial claim - Interpretationown data
Naïve CD4+ T cells display a comparable capacity to differentiate into Th17 cells in response to either classic or trans IL-6 receptor signaling.
“Thus, naïve CD4+ T cells display a comparable capacity to differentiate into Th17 cells in response to either classic or trans IL-6 receptor signaling.”
Quote in the paperSubstantial claim - Interpretationown data
Persistent IL-6 signaling is required to maintain the Th17 phenotype in vivo.
“Together, these findings establish that persistent IL-6 signaling is required to maintain the Th17 phenotype in vivo”
Quote in the paperSubstantial claim - Interpretationown data
Loss of Th17 phenotype is not due to conversion to Treg in the absence of IL-6 signaling.
“suggesting that loss of Th17 phenotype is not due to conversion to Treg in the absence of IL-6 signaling”
Quote in the paperSubstantial claim - Interpretationown data
High IL-6 expression in the colon promoted classic, or cis, rather than trans receptor signaling that was required for maintenance of Th17 cells.
“High IL-6 expression in the colon promoted classic, or cis, rather than trans receptor signaling that was required for maintenance of Th17 cells.”
Quote in the paperSubstantial claim - Interpretationown data
Classic rather than trans IL-6 receptor signaling is favored for maintenance of the Th17 program in the colon microenvironment.
“and that classic rather than trans IL-6 receptor signaling is favored for maintenance of the Th17 program in the colon microenvironment”
Quote in the paperSubstantial claim - Interpretationown data
Trans-signaling in the absence of membrane bound IL-6Rα is not sufficient to induce development of a pathogenic Th17 response.
“trans-signaling in the absence of membrane bound IL-6Rα is not sufficient to induce development of a pathogenic Th17 response”
Quote in the paperSubstantial claim - Interpretationown data
IL-6 is required in the maintenance of Th17 responses required for chronic disease progression.
“these findings support a role for IL-6 in the maintenance of Th17 responses required for chronic disease progression”
Quote in the paperSubstantial claim - Interpretationown data
Reduction in disease in Il6ra−/− recipients was not due to an increase in Treg cells.
“suggesting that reduction in disease in Il6ra−/− recipients was not due to an increase in Treg cells”
Quote in the paperSubstantial claim - Interpretationown data
Ongoing IL-6 signaling is required to maintain Th17 program stability.
“further indicating that ongoing IL-6 signaling is required to maintain Th17 program stability.”
Quote in the paperSubstantial claim - Interpretationown data
IL-6 signaling in naïve CD4+ T cells is required for the pathogenesis of IBD.
“Together, these results indicate that IL-6 signaling in naïve CD4+ T cells is required for the pathogenesis of IBD”
Quote in the paperSubstantial claim - Interpretationreasoning
Competition from intestinal innate, epithelial and stromal cells, which can express gp130 and signal in trans, appeared to prevent IL-6 trans-signaling in Th17 cells.
“Rather, competition from intestinal innate, epithelial and stromal cells, all of which can express gp130 and can signal in trans, appeared to prevent IL-6 trans-signaling in Th17 cells.”
Quote in the paperSubstantial claim - Premisecitation
IL-6Rα and gp130 are downregulated upon T cell activation.
“we and others have found that IL-6Rα and gp130 are downregulated upon T cell activation (31)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Hunter CA, Jones SA, IL-6 as a keystone cytokine in health and disease. 16, 448– 457 (2015). 25898198 source
- Interpretationreasoning
Competition for their respective inductive/maintenance cytokine is a major contributor to Th17 versus Treg pool size both at homeostasis and during the emergence and subsidence of an antigen-driven inflammatory response.
“this suggests that competition for their respective inductive/maintenance cytokine is a major contributor to Th17 versus Treg pool size both at homeostasis and during the emergence and subsidence of an antigen-driven inflammatory response.”
Quote in the paperSubstantial claim- Rests on an assumption: IL-6 promotes the development of Th17 cells and inhibits Tregs, while IL-2 promotes the development of Tregs and inhibits Th17 cells.
- Interpretationown data
Mechanisms controlling the expression of gp130 by effector T cells are limiting for Th17 maintenance, irrespective of IL-6Rα expression and the local balance of free versus sIL-6Rα-bound IL-6.
“suggests that mechanisms controlling the expression of gp130 by effector T cells are limiting for Th17 maintenance—irrespective of the expression of IL-6Rα and the local balance of free versus sIL-6Rα-bound IL-6.”
Quote in the paperSubstantial claim - Interpretationreasoning
Inhibiting classic signaling and thus the protective effects of IL-6 may exacerbate disease.
“suggests that inhibiting classic signaling and thus the protective effects of IL-6 may exacerbate disease.”
Quote in the paperSubstantial claim - Interpretationreasoning
IL-6-dependent maintenance of a pool of Th17 cells provides precursors from which pathogenic Th1-like cells can arise.
“However, it also appears that the IL-6–dependent maintenance of a pool of Th17 cells provides precursors from which pathogenic Th1-like cells can arise.”
Quote in the paperSubstantial claim - Interpretationreasoning
The requirement for paracrine IL-6 in Th17 cells draws a parallel between Th17 cells and Treg cells.
“draws a further parallel between Th17 cells and Treg cells (62).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [62] Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM, Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity. 24, 677– 688 (2006). 16782025 source
- Interpretationreasoning
For both Th17 and Treg lineages, dependence on a single cytokine as both developmental inducer and maintenance factor renders them particularly susceptible to lineage instability.
“For both lineages, the dependence on a single cytokine as both developmental inducer and maintenance factor renders them particularly susceptible to lineage instability.”
Quote in the paperSubstantial claim - Interpretationreasoning
In the colon, a high IL-6-sIL-6Rα ratio due to high local production of IL-6 favored sufficiently high concentrations of free IL-6 to enable classic signaling to T cells co-expressing membrane-bound IL-6Rα and gp130.
“At least in the colon, a high IL-6–sIL-6Rα ratio due to high local production of IL-6 favored sufficiently high concentrations of free IL-6 to enable classic signaling to the relatively small percentage of T cells co-expressing membrane bound IL-6Rα and gp130.”
Quote in the paperSubstantial claim - Interpretationreasoning
Persistent classic IL-6 receptor signaling that sustains intestinal Th17 responses may enhance barrier function to restrain disease.
“persistent classic IL-6 receptor signaling that sustains intestinal Th17 responses may enhance barrier function to restrain disease.”
Quote in the paperSubstantial claim - Interpretationcitation
This downregulation would appear to favor a shift from classic to trans IL-6 signaling in developing Th17 cells.
“which would appear to favor a shift from classic to trans IL-6 signaling in developing Th17 cells.”
Quote in the paperNot a substantial claim - Interpretationown data
Complete buffering by sgp130 is unlikely to explain why IL-6 trans-signaling is insufficient for Th17 development/maintenance in vivo, because sIL-6Rα was in substantial excess in colitic mice.
“The reasons for this are unclear, but are unlikely to involve complete buffering by sgp130, as sIL-6Rα was in substantial excess in colitic mice.”
Quote in the paperSubstantial claim
- May combine two claims. 30
- Classified as probably not a substantial claim. 21
May combine two claims.
Interpretationown dataOngoing IL-6 signaling is indispensable and foundational, acting upstream of IL-23 via its unique function to sustain RORγt expression and thereby IL-23R expression.
“Although it has been reported that IL-23 signaling is important for the maintenance of Th17 cells (18, 19, 21), we find that ongoing IL-6 signaling is indispensable and foundational, acting upstream of IL-23 via its unique function to sustain RORγt expression and thereby IL-23R expression.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [18] Elson CO, Monoclonal anti–interleukin 23 reverses active colitis in a T cell–mediated model in mice. 132, 2359– 2370 (2007). 17570211 source
- cites [19] Lee YK, Late developmental plasticity in the T helper 17 lineage. Immunity. 30, 92– 107 (2009). 19119024 PMC3607320 source
The citation attaches to the reported importance of IL-23 signaling for Th17 maintenance, not to the citing authors’ finding about ongoing IL-6 signaling. In Results (‘TGF-β Is Required for Maintenance of IL-17 Expression by Th17 Cells’), the source says the opposite: IL-23 appears dispensable for Th17 maintenance, whereas continuous TGF-β signaling is needed to maintain IL-17 expression. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [21] Stritesky GL, Yeh N, Kaplan MH, IL-23 promotes maintenance but not commitment to the Th17 lineage. J. Immunol 181, 5948– 5955 (2008). 18941183 PMC2678905 source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationIL-23 has been reported to be a trophic factor for Th17 cells, but IL-23 signaling also promotes the transdifferentiation of Th17 cells to Th1-like cells.
“IL-23 has been reported to be a trophic factor for Th17 cells (19, 23, 65), but IL-23 signaling also promotes the transdifferentiation of Th17 cells to Th1-like cells (19, 26)”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [19] Lee YK, Late developmental plasticity in the T helper 17 lineage. Immunity. 30, 92– 107 (2009). 19119024 PMC3607320 source
The Introduction reports that IL-23 had been speculated to enhance or maintain the Th17 phenotype, but the paper's Results find IL-23 dispensable for Th17 maintenance. The Results also show IL-23 promoting a shift toward IFN-γ-producing, Th1-like progeny, specifically when TGF-β is low or absent; the citing sentence omits that condition. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [23] Hirota K, Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol. 12, 255– 263 (2011). 21278737 PMC3040235 source
The Results section, “Effector deviation depends on IL-23 signalling” (page unavailable), reports that loss of IL-23 reduced the proportion of fate-marked Th17 cells and prevented their acquisition of IFN-γ production and T-bet expression. This supports IL-23’s role in deviation toward a Th1-like state. The paper describes IL-23 as important for effector differentiation, but does not establish the more specific claim that it is a trophic factor for Th17 cells. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [65] Murphy KM, Stockinger B, Effector T cell plasticity: flexibility in the face of changing circumstances. Nat Immunol. 11, 674– 680 (2010). 20644573 PMC3249647 source
The Abstract describes IL-23 as required for IL-17-producing CD4+ T cells, broadly consistent with a supportive role, but does not call it a trophic factor. In “Circuit rules” (page not provided), the paper says TH17 cells can transition to TH1 cells, at least in vitro; it does not say IL-23 signaling promotes that transition. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataGSEA using a previously defined Th17-Th1 gene set identified significant enrichment of Th1-related genes in Il6ra−/− T cells ex vivo, while the transcriptome of WT T cells was enriched for a subset of genes related to Th17 cells ex vivo.
“Gene set enrichment analysis (GSEA) using a previously defined Th17–Th1 gene set (57) identified significant enrichment of Th1-related genes in Il6ra−/− T cells ex vivo (Fig. 6E, right and Supplementary Fig. 7). Conversely, and in accord with our previous findings, the transcriptome of WT T cells was enriched for a subset of genes related to Th17 cells ex vivo”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [57] Wei G, Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity. 30, 155– 167 (2009). 19144320 PMC2722509 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIntestinal tissues are enriched in both Th17 and Treg cells and are subject to ongoing antigenic stimulation from the intestinal microbiome.
“This is of particular importance in intestinal tissues, which are enriched in both Th17 and Treg cells and are subject to ongoing antigenic stimulation from the intestinal microbiome (70).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [70] Maynard CL, Elson CO, Hatton RD, Weaver CT, Reciprocal interactions of the intestinal microbiota and immune system. Nature. 489, 231– 241 (2012). 22972296 PMC4492337 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIL-2 signaling inhibits expression of Il6ra and Il6st (gp130).
“IL-2 signaling has been shown to inhibit expression of Il6ra and Il6st (gp130)(76)”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [76] Liao W, Lin J-X, Wang L, Li P, Leonard WJ, Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nat Immunol. 12, 551– 559 (2011). 21516110 PMC3304099 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIL-6Rα is downregulated primarily by cleavage of the extracellular domain by ADAM10 and ADAM17 in humans, or only ADAM10 in mice.
“IL-6Rα appears to be downregulated primarily by cleavage of the extracellular domain by the metalloproteinases ADAM10 and ADAM17 in humans (74), or only ADAM 10 in mice (75)”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [74] Matthews V, Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE). J. Biol. Chem 278, 38829– 38839 (2003). 12832423 source
- cites [75] Garbers C, Species specificity of ADAM10 and ADAM17 proteins in interleukin-6 (IL-6) trans-signaling and novel role of ADAM10 in inducible IL-6 receptor shedding. J. Biol. Chem 286, 14804– 14811 (2011). 21454673 PMC3083187 source
May combine two claims.
PremisecitationTh17 cells assisted the development and/or survival of pathogenic Th1 cells that were unable to drive disease on their own.
“our previous studies showed that Th17 cells assisted the development and/or survival of pathogenic Th1 cells that were unable to drive disease on their own (73).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [73] Harbour SN, Maynard CL, Zindl CL, Schoeb TR, Weaver CT, Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc. Natl. Acad. Sci. U.S.A 112, 7061– 7066 (2015). 26038559 PMC4460486 source
May combine two claims.
PremisecitationThe IL6RA variant rs2228145 leads to increased proteolytic cleavage of IL-6Rα, reducing membrane-bound IL-6Rα and increasing serum levels.
“The IL6RA variant rs2228145, which leads to increased proteolytic cleavage of IL-6Rα and thus a reduction in membrane-bound IL-6Rα in favor of increased serum levels (79)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [79] Garbers C, The interleukin-6 receptor Asp358Ala single nucleotide polymorphism rs2228145 confers increased proteolytic conversion rates by ADAM proteases. Biochim. Biophys. Acta 1842, 1485– 1494 (2014). 24878322 source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationClassic and trans-signaling promote anti- and pro-inflammatory responses, respectively.
“This is in line with the view that classic and trans-signaling promote anti- and pro-inflammatory responses, respectively (85)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [85] Rose-John S, IL-6 Trans-Signaling via the Soluble IL-6 Receptor: Importance for the Pro-Inflammatory Activities of IL-6. Int. J. Biol. Sci 8, 1237– 1247 (2012). 23136552 PMC3491447 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSubsequent studies established an essential role for the IL-23-Th17 axis in disease pathogenesis.
“whereas subsequent studies established an essential role for the IL-23–Th17 axis in disease pathogenesis (15, 72).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [15] Ahern PP, Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity. 33, 279– 288 (2010). 20732640 PMC3078329 source
The Results section ('IL-23R Expression on T Cells Is Required for Intestinal but Not Systemic Inflammation'; page unavailable) finds that T-cell IL-23R signaling is required for intestinal inflammation and is associated with reduced Th17-related responses when absent. The Discussion says IL-23-dependent Th17-like cells are suggested to play an important role in pathogenesis; it does not establish that the entire IL-23–Th17 axis is essential to disease pathogenesis generally. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [72] Hue S, Interleukin-23 drives innate and T cell–mediated intestinal inflammation. J Exp Med. 203, 2473– 2483 (2006). 17030949 PMC2118132 source
The Abstract reports a crucial role for IL-23 in mouse models of intestinal inflammation. The Discussion, however, says IL-23–driven Th17 responses may be important but are one of several mechanisms contributing to colitis; it does not establish that the combined IL-23–Th17 axis is essential. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationThe IL6RA variant rs2228145 is associated with reduced risk of both RA and IBD.
“is associated with reduced risk of both RA (77) and IBD (78).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [77] Eyre S, High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet. 44, 1336– 1340 (2012). 23143596 PMC3605761 source
The IL6R discussion (page unavailable) reports an association with rheumatoid arthritis and says an IL6R-linked allele is protective (OR=0.9). This citation is attached to the RA portion of the sentence, not the IBD portion. Our copy names rs8192284 and the linked rs4129267, but does not identify either as rs2228145, so it does not establish the claim for that specific variant. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [78] Parisinos CA, Variation in interleukin 6 receptor gene associates with risk of Crohn’s disease and ulcerative colitis. YGAST, 1– 17 (2018). PMC6083435 29775600 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEarly seminal studies identified a definitive link between Th1 cells and colitis.
“Early seminal studies identified a definitive link between Th1 cells and colitis (47, 71)”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [47] Powrie F, Leach MW, Mauze S, Caddle LB, Coffman RL, Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. International Immunology. 5, 1461– 1471 (1993). 7903159 source
- cites [71] Powrie F, Correa-Oliveira R, Mauze S, Coffman RL, Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity. J Exp Med. 179, 589– 600 (1994). 7905019 PMC2191378 source
May combine two claims.
PremisecitationIn tissue-specific immune-mediated diseases including IBD, therapies that inhibit IL-6 signaling have not gained clinical use despite evidence that antibodies targeting IL-6 or IL-6Rα may have efficacy.
“This is in contrast to tissue-specific immune-mediated diseases, including IBD, where therapies that inhibit IL-6 signaling have not gained clinical use despite evidence that antibodies targeting IL-6 or IL-6Rα may have efficacy (83).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [83] Ito H, A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease. YGAST. 126, 989– 96– discussion 947 (2004). 15057738 source
The Clinical Response to Treatment section (page not supplied) reports a higher response rate with an anti-IL-6 receptor antibody than with placebo in active Crohn’s disease, supporting possible efficacy in IBD. The paper does not establish whether IL-6-inhibiting therapies gained clinical use, nor does its trial address tissue-specific immune-mediated diseases beyond Crohn’s disease. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataWT and Il6ra−/− Th17 cells repopulate the colon equivalently at 4 weeks post transfer, indicating no defect in the ability of Il6ra−/− Th17 cells to traffic to the colon.
“WT and Il6ra−/− Th17 cells repopulate the colon equivalently at 4 weeks post transfer (Fig. 4G–H), indicating no defect in the ability of Il6ra−/− Th17 cells to traffic to the colon.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCo-transfer of wild type Th17 cells with IL-6Rα-deficient Th17 cells induced colitis but was unable to rescue phenotype loss of the latter.
“Co-transfer of wild type Th17 cells with IL-6Rα–deficient Th17 cells induced colitis but was unable to rescue phenotype loss of the latter.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataColon explant cultures showed that IL-6 was in molar excess relative to sIL-6Rα in all groups, while sIL-6Rα was in excess of sgp130, enabling both classic and trans-signaling in the colon microenvironment.
“colon explant cultures showed that IL-6 was in molar excess relative to sIL-6Rα in all groups (Fig. 4E), while sIL-6Rα was again in excess of sgp130 (Fig. 4F)—enabling both classic and trans-signaling in the colon microenvironment.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataReduced disease in recipients of Il6ra−/− Th17 cells was associated with a significant loss of IL-17A+ and IL-17A+IFN-γ+ T cells recovered from the CLP, with a concomitant increase in the percentage of IFN-γ+ T cells.
“The reduced disease observed in recipients of Il6ra−/− Th17 cells was associated with a significant loss of IL-17A+ and IL-17A+IFN-γ+ T cells recovered from the CLP, with a concomitant increase in the percentage of IFN-γ+ T cells”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIl6ra−/− CLP CD4+ T cells were enriched for Th1 genes, while expression of Th17-related genes was associated with WT, rather than Il6ra−/− CLP CD4+ T cells.
“We find here that Il6ra−/− CLP CD4+ T cells were enriched for the aforementioned Th1 genes. Conversely, expression of Th17-related genes was associated with WT, rather than Il6ra−/− CLP CD4+ T cells”
Quote in the paperSubstantial claimMay combine two claims.
FindingreasoningIL-6 trans-signaling was intact and comparable in WT and IL-6Rα-deficient T cells recovered from colitic mice, but was substantially diminished, reflecting diminished gp130 expression and/or signaling competency.
“Although IL-6 trans-signaling was intact and comparable in WT and IL-6Rα-deficient T cells recovered from colitic mice, it was substantially diminished, reflecting diminished gp130 expression and/or signaling competency.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingnone givenTh17 cells have a critical requirement for paracrine IL-6 in both their induction and maintenance.
“The finding of a critical requirement for paracrine IL-6 in both the induction and maintenance of Th17 cells”
Quote in the paperSubstantial claimMay combine two claims.
FindingreasoningIL-6 trans-signaling was insufficient for either Th17 development or maintenance in vivo, despite elevated sIL-6Rα.
“it was insufficient for either Th17 development or maintenance in vivo, despite elevated sIL-6Rα.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataClassic IL-6 receptor signaling in WT cells, which promotes retention of the Th17 phenotype, preferentially induces pY-STAT3 without pY-STAT1.
“Moreover, classic IL-6 receptor signaling in WT cells, which promotes retention of the Th17 phenotype, preferentially induces pY-STAT3 without pY-STAT1.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThere is an absolute requirement for persistent IL-6 signaling to maintain the Th17 genetic program, and thus Th17 cells.
“Here, we report that in addition to its key role in Th17 cell induction (3, 4), there is an absolute requirement for persistent IL-6 signaling to maintain the Th17 genetic program, and thus Th17 cells.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [3] Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B, TGFβ in the Context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 24, 179– 189 (2006). 16473830 source
- cites [4] Bettelli E, Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 441, 235– 238 (2006). 16648838 source
May combine two claims.
Interpretationown dataEnforced RORγt expression in IL-6R-deficient Th17 cells supports maintenance of the Th17 program but does not completely prevent Th1 transdifferentiation.
“Enforced RORγt expression in IL-6R-deficient Th17 cells supports maintenance of the Th17 program but does not completely prevent Th1 transdifferentiation”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataIL-6 receptor signaling in these cells is not required for development of an intact Th1 pathway but is essential for control of pathogenic T cells displaying a Th17 program.
“Thus, IL-6 receptor signaling in these cells is not required for development of an intact Th1 pathway but is essential for control of pathogenic T cells displaying a Th17 program”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe requirement for IL-6 signaling is not related to effects on cell cycle or cell survival, but instead appears to be intrinsic to Th17 lineage maintenance.
“the requirement for IL-6 signaling is not related to effects on cell cycle or cell survival, but instead appears to be intrinsic to Th17 lineage maintenance.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataOngoing classic IL-6 signaling underpins the Th17 program and is required for Th17 cell maintenance and function.
“Thus, ongoing classic IL-6 signaling underpins the Th17 program and is required for Th17 cell maintenance and function.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningOngoing classic IL-6 signaling in Th17 cells is required to maintain tyrosine phosphorylation of STAT3, and thus IL-6-induced STAT3 activation is critical for both the development and maintenance of Th17 cells.
“Therefore, ongoing classic IL-6 signaling in Th17 cells is required to maintain tyrosine phosphorylation of STAT3, and thus IL-6-induced STAT3 activation is critical for both the development and maintenance of Th17 cells.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataIn the absence of IL-6 sustained signaling, Th17 cells were unstable, indicating that ongoing classic IL-6 signal is required to maintain a Th17 response.
“Thus, in the absence of IL-6 sustained signaling, Th17 cells were unstable, indicating that ongoing, classic IL-6 signal is required to maintain a Th17 response.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningTh17 cells require tonic or intermittent classic IL-6 signaling, which shifts from a STAT3-STAT1 output during early development to a pure STAT3 output in mature cells.
“Our finding that Th17 cells require tonic or intermittent classic IL-6 signaling, which shifts from a STAT3–STAT1 output during early development to a pure STAT3 output in mature cells”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIL-6 can amplify inflammation-induced injury to a variety of cells and tissues.
“Given that IL-6 can amplify inflammation-induced injury to a variety of cells and tissues”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Hunter CA, Jones SA, IL-6 as a keystone cytokine in health and disease. 16, 448– 457 (2015). 25898198 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTreg cells require IL-2 for both their development and maintenance.
“Treg cells require IL-2 for both their development and maintenance (69)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [69] Malek TR, The biology of interleukin-2. Annu. Rev. Immunol 26, 453– 479 (2008). 18062768 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSurface expression of gp130 is downregulated by internalization, alternative splicing of the encoding mRNA to favor the secreted form, and/or other unidentified mechanisms.
“Surface expression of gp130 is downregulated by internalization, alternative splicing of the encoding mRNA to favor the secreted form, and/or other unidentified mechanisms (31).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Hunter CA, Jones SA, IL-6 as a keystone cytokine in health and disease. 16, 448– 457 (2015). 25898198 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenGender and age matched male and female mice were used.
“Gender and aged matched male and female mice were used”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTreg cells are unable to produce IL-2 themselves.
“but are unable to produce IL-2 themselves.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [69] Malek TR, The biology of interleukin-2. Annu. Rev. Immunol 26, 453– 479 (2008). 18062768 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTreg cells are thought to rely on production of IL-2 by activated naive or other effector T cells.
“Instead, they are thought to rely on production of IL-2 by activated naive or other effector T cells (69)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [69] Malek TR, The biology of interleukin-2. Annu. Rev. Immunol 26, 453– 479 (2008). 18062768 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenLittermate comparisons were used for all experiments where possible.
“Littermate comparisons were used for all experiments where possible.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningClassic signaling plays a dominant role in Th17 maintenance in the intestine both at baseline and in the diseased state.
“consistent with a dominant role for classic signaling in Th17 maintenance in this tissue both at baseline and in the diseased state.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningRetention or re-expression of IL-6Rα and gp130 by T cells appears to be key in determining which cells are competent to retain the Th17 program and by what mode of IL-6R signaling.
“which now appear to be key in determining which cells are competent to retain the Th17 program and by what mode of IL-6R signaling.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll animals were bred and maintained in accordance with institutional animal care and use committee regulations.
“All animals were bred and maintained in accordance with institutional animal care and use committee regulations.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll experiments were replicated as presented in the figure legends.
“All experiments were replicated as presented in the figure legends.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenExperiments were not blinded to investigators.
“Experiments were not blinded to investigators”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenSamples for histopathological analyses were blinded prior to scoring.
“samples for histopathological analyses were blinded prior to scoring.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Study design and conductnone givenGroup sizes were the minimum required to detect statistically significant differences based on previous experience.
“Group sizes were the minimum required to detect statistically significant differences based on previous experience.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAnimals were randomly assigned into different groups.
“animals were randomly assigned into different groups.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationSamples were scored by a pathologist in a blinded fashion.
“Samples were scored by a pathologist in a blinded fashion as previously described (86).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [86] Maynard CL, Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3− precursor cells in the absence of interleukin 10. Nat Immunol. 8, 931– 941 (2007). 17694059 source
The paper relies on this without support.
IL-6 promotes the development of Th17 cells and inhibits Tregs, while IL-2 promotes the development of Tregs and inhibits Th17 cells.
“IL-6 promotes the development of Th17 cells and inhibits Tregs, while IL-2 promotes the development of Tregs and inhibits Th17 cells”
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BackgroundInfluentialIL-6 as a keystone cytokine in health and disease
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BackgroundIL-17 family cytokines and the expanding diversity of effector T cell lineages
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BackgroundSelf-citationIL-21 initiates an alternative pathway to induce proinflammatory TH17 cells
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Reciprocal interactions of the intestinal microbiota and immune system
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BackgroundSTAT3 Regulates Cytokine-mediated Generation of Inflammatory Helper T Cells
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BackgroundInfluentialTh17: An Effector CD4 T Cell Lineage with Regulatory T Cell Ties
Weaver, C. T., Harrington, L. E., Mangan, P. R., Gavrieli, M., & Murphy, K. M. (2006) · Immunity · doi:10.1016/j.immuni.2006.06.002 · Cited by 1,422 · cited 1× · see citing works
“The finding of a critical requirement for paracrine IL-6 in both the induction and maintenance of TH17 cells draws a further parallel between TH17 cells and Treg cells (61).”
BackgroundSelf-citationGenome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways
Nair, R. P., Duffin, K. C., Helms, C. A., Ding, J., Stuart, P. E., Goldgar, D. E., Gudjonsson, J. E., Li, Y., Tejasvi, T., Feng, B., et al. (2009) · Nature Genetics · doi:10.1038/ng.311 · Cited by 1,414 · see citing works
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“An excess of sIL6Ra, however, is a marker of active inflammation (43) and allows for trans-signaling to a wide variety of cell targets, and amplifies inflammatory responses through the recruitment and activation of mononuclear cells (44, 45).”
BackgroundFate mapping of IL-17-producing T cells in inflammatory responses
Hirota, K., Duarte, J. H., Veldhoen, M., Hornsby, E., Li, Y., Cua, D. J., Ahlfors, H., Wilhelm, C., Tolaini, M., Menzel, U., et al. (2011) · Nature Immunology · doi:10.1038/ni.1993 · Cited by 1,176 · cited 12× · see citing works
“This transdifferentiation of TH17 cells is dependent on both STAT4 and T-bet (19, 23, 26, 27).”
BackgroundResultInfluentialInduction and molecular signature of pathogenic TH17 cells
Lee, Y., Awasthi, A., Yosef, N., Quintana, F. J., Xiao, S., Peters, A., Wu, C., Kleinewietfeld, M., Kunder, S., Hafler, D. A., et al. (2012) · Nature Immunology · doi:10.1038/ni.2416 · Cited by 1,174 · see citing works
A Validated Regulatory Network for Th17 Cell Specification
Ciofani, M., Madar, A., Galan, C., Sellars, M., Mace, K., Pauli, F., Agarwal, A., Huang, W., Parkurst, C. N., Muratet, M., et al. (2012) · Cell · doi:10.1016/j.cell.2012.09.016 · Cited by 1,160 · cited 2× · see citing works
“8 of 16 activator in TH17 cells, whereas Rorc is thought to be an expression modulator (9).”
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“Gene set enrichment analysis (GSEA) using a previously defined Th17–Th1 gene set (57) identified significant enrichment of Th1-related genes in Il6ra T cells ex vivo (Fig.”
MethodEmery, P., Keystone, E., Tony, H. P., Cantagrel, A., van Vollenhoven, R., Sanchez, A., Alecock, E., Lee, J., & Kremer, J. (2008) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2008.092932 · Cited by 1,104 · see citing works
Malek, T. R. (2008) · Annual Review of Immunology · doi:10.1146/annurev.immunol.26.021607.090357 · Cited by 1,079 · cited 2× · see citing works
“Treg cells require IL-2 for both their development and maintenance (69) but are unable to produce IL-2 themselves.”
BackgroundPowrie, F., Leach, M. W., Mauze, S., Caddie, L. B., & Coffman, R. L. (1993) · International Immunology · doi:10.1093/intimm/5.11.1461 · Cited by 1,078 · cited 2× · see citing works
“WT and Il6ra naïve T cells were used as donors in the CD4 CD45RB T cell transfer colitis model (47).”
BackgroundMethodMcGeachy, M. J., Chen, Y., Tato, C. M., Laurence, A., Joyce-Shaikh, B., Blumenschein, W. M., McClanahan, T. K., O'Shea, J. J., & Cua, D. J. (2009) · Nature Immunology · doi:10.1038/ni.1698 · Cited by 1,074 · see citing works
Late Developmental Plasticity in the T Helper 17 Lineage
Lee, Y. K., Turner, H., Maynard, C. L., Oliver, J. R., Chen, D., Elson, C. O., & Weaver, C. T. (2009) · Immunity · doi:10.1016/j.immuni.2008.11.005 · Cited by 1,053 · see citing works
Self-citationFalse discovery rates: a new deal
Stephens, M. (2016) · Biostatistics · doi:10.1093/biostatistics/kxw041 · Cited by 1,053 · see citing works
Rose-John, S. (2012) · International Journal of Biological Sciences · doi:10.7150/ijbs.4989 · Cited by 1,040 · cited 1× · see citing works
“This is in line with the view that classic and trans-signaling promote anti- and proinflammatory responses, respectively (84), and suggests that inhibiting classic signaling and, thus, the protective effects of IL-6 may exacerbate disease.”
BackgroundThe alarmin IL-33 promotes regulatory T-cell function in the intestine
Schiering, C., Krausgruber, T., Chomka, A., Fröhlich, A., Adelmann, K., Wohlfert, E. A., Pott, J., Griseri, T., Bollrath, J., Hegazy, A. N., et al. (2014) · Nature · doi:10.1038/nature13577 · Cited by 1,007 · see citing works
Interleukin-23 drives innate and T cell–mediated intestinal inflammation
Hue, S., Ahern, P., Buonocore, S., Kullberg, M. C., Cua, D. J., McKenzie, B. S., Powrie, F., & Maloy, K. J. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20061099 · Cited by 823 · see citing works
Hurst, S. M., Wilkinson, T. S., McLoughlin, R. M., Jones, S., Horiuchi, S., Yamamoto, N., Rose-John, S., Fuller, G. M., Topley, N., & Jones, S. A. (2001) · Immunity · doi:10.1016/s1074-7613(01)00151-0 · Cited by 811 · cited 1× · see citing works
“An excess of sIL-6R, however, is a marker of active inflammation (43) and allows for trans-signaling to a wide variety of cell targets and amplifies inflammatory responses through the recruitment and activation of mononuclear cells (44, 45).”
BackgroundSelf-citationYokota, S., Imagawa, T., Mori, M., Miyamae, T., Aihara, Y., Takei, S., Iwata, N., Umebayashi, H., Murata, T., Miyoshi, M., et al. (2008) · The Lancet · doi:10.1016/s0140-6736(08)60454-7 · Cited by 789 · see citing works
Interleukin 6 and its receptor: ten years later
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A protective function for interleukin 17A in T cell–mediated intestinal inflammation
O'Connor Jr, W., Kamanaka, M., Booth, C. J., Town, T., Nakae, S., Iwakura, Y., Kolls, J. K., & Flavell, R. A. (2009) · Nature Immunology · doi:10.1038/ni.1736 · Cited by 756 · see citing works
Diverse Targets of the Transcription Factor STAT3 Contribute to T Cell Pathogenicity and Homeostasis
Durant, L. R., Watford, W. T., Ramos, H. L., Laurence, A. D. J., Vahedi, G., Wei, L., Takahashi, H., Sun, H., Kanno, Y., Powrie, F. M., et al. (2010) · Immunity · doi:10.1016/j.immuni.2010.05.003 · Cited by 731 · see citing works
Dynamic regulatory network controlling TH17 cell differentiation
Yosef, N., Shalek, A. K., Gaublomme, J. T., Jin, H., Lee, Y., Awasthi, A., Wu, C., Karwacz, K., Xiao, S., Jorgolli, M., et al. (2013) · Nature · doi:10.1038/nature11981 · Cited by 682 · cited 1× · see citing works
“STAT3 induces the expression of Th17-related genes including Il17a, Il17f, Il22, Il23r and the master transcription factor Rorc (6-8), which itself is a positive regulator of key Th17 genes and a negative regulator of alternative lineage fates (9-12).”
Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci
Reveille, J. D., Jin, R., Zhou, X., Diekman, L., Sims, A. M., Danoy, P., Leo, P., Bradbury, L. A., Doan, T., Dowling, A., et al. (2010) · Nature Genetics · doi:10.1038/ng.513 · Cited by 669 · see citing works
Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses.
Jostock, T., Müllberg, J., Özbek, S., Atreya, R., Blinn, G., Voltz, N., Fischer, M., Neurath, M., & Rose-John, S. (2001) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2001.01867.x · Cited by 665 · see citing works
High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis
Syndicate, B. I. R. A. G. A. G. S., Eyre, S., Wellcome Trust Case Control Consortium, Bowes, J., Diogo, D., Lee, A., Barton, A., Martin, P., Zhernakova, A., Stahl, E., et al. (2012) · Nature Genetics · doi:10.1038/ng.2462 · Cited by 653 · see citing works
Hexameric Structure and Assembly of the Interleukin-6/IL-6 α-Receptor/gp130 Complex
Boulanger, M. J., Chow, D., Brevnova, E. E., & García, K. C. (2003) · Science · doi:10.1126/science.1083901 · Cited by 647 · cited 1× · see citing works
“Classic, or cis, IL-6 receptor signaling occurs in cells that express both membranebound IL-6R and the signal transducing component, gp130, which bind IL-6 in a hexameric complex where IL-6, IL-6R, and gp130 exist in a 2:2:2 stoichiometry (32).”
BackgroundIto, H., Takazoe, M., Fukuda, Y., Hibi, T., Kusugami, K., Andoh, A., Matsumoto, T., Yamamura, T., Azuma, J., & Nishimoto, N. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.01.012 · Cited by 636 · see citing works
Powrie, F., Correa-Oliveira, R., Mauze, S., & Coffman, R. L. (1994) · The Journal of experimental medicine · doi:10.1084/jem.179.2.589 · Cited by 613 · see citing works
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Self-citationYang, X.-P., Ghoreschi, K., Steward-Tharp, S. M., Rodriguez-Canales, J., Zhu, J., Grainger, J. R., Hirahara, K., Sun, H.-W., Wei, L., Vahedi, G., et al. (2011) · Nature Immunology · doi:10.1038/ni.1995 · Cited by 583 · see citing works
Interleukin-23 Drives Intestinal Inflammation through Direct Activity on T Cells
Ahern, P. P., Schiering, C., Buonocore, S., McGeachy, M. J., Cua, D. J., Maloy, K. J., & Powrie, F. (2010) · Immunity · doi:10.1016/j.immuni.2010.08.010 · Cited by 528 · see citing works
The soluble interleukin‐6 receptor is generated by shedding
Müllberg, J., Schooltink, H., Stoyan, T., Günther, M., Graeve, L., Buse, G., Mackiewicz, A. A., Heinrich, P. C., & Rose‐John, S. (1993) · European Journal of Immunology · doi:10.1002/eji.1830230226 · Cited by 507 · see citing works
Effector T cell plasticity: flexibility in the face of changing circumstances
Murphy, K. M., & Stockinger, B. (2010) · Nature Immunology · doi:10.1038/ni.1899 · Cited by 482 · cited 2× · see citing works
“In contrast to Th1 and Th2 cells, Th17 cells show substantially greater plasticity (19, 23, 65).”
BackgroundLiao, W., Lin, J.-X., Wang, L., Li, P., & Leonard, W. J. (2011) · Nature Immunology · doi:10.1038/ni.2030 · Cited by 474 · cited 1× · see citing works
“Although IL-2 signaling has been shown to inhibit expression of Il6ra and Il6st (gp130) (75), little is known about conditions that promote retention or reexpression of IL-6R and gp130 by T cells, which now appear to be a key in determining which cells are competent to retain in the TH17 program and by what mode of I…”
BackgroundMonoclonal Anti–Interleukin 23 Reverses Active Colitis in a T Cell–Mediated Model in Mice
Elson, C. O., Cong, Y., Weaver, C. T., Schoeb, T. R., McClanahan, T. K., Fick, R. B., & Kastelein, R. A. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.03.104 · Cited by 453 · see citing works
Self-citationLeppkes, M., Becker, C., Ivanov, I. I., Hirth, S., Wirtz, S. J., Neufert, C. F., Pouly, S., Murphy, A. J., Valenzuela, D. M., Yancopoulos, G. D., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.10.018 · Cited by 445 · cited 1× · see citing works
“Thus, IL-6 receptor signaling in these cells is not required for development of an intact TH1 pathway but is essential for control of pathogenic T cells displaying a TH17 program (15, 48).”
BackgroundFoxp3 Inhibits RORγt-mediated IL-17A mRNA Transcription through Direct Interaction with RORγt*
Ichiyama, K., Yoshida, H., Wakabayashi, Y., Chinen, T., Saeki, K., Nakaya, M., Takaesu, G., Hori, S., Yoshimura, A., & Kobayashi, T. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801286200 · Cited by 438 · see citing works
Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis
Harbour, S. N., Maynard, C. L., Zindl, C. L., Schoeb, T. R., & Weaver, C. T. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1415675112 · Cited by 427 · cited 3× · see citing works
“A recent study from our group reconciled these findings by demonstrating that TH1-like cells, which derived from TH17 precursors contingent on intact IL-23–induced STAT4 activation and T-bet expression, were critical for colitis development (60).”
BackgroundResultSelf-citationIL-23 Promotes Maintenance but Not Commitment to the Th17 Lineage
Stritesky, G. L., Yeh, N., & Kaplan, M. H. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.9.5948 · Cited by 417 · cited 1× · see citing works
“Although it has been reported that IL-23 signaling is important for the maintenance of TH17 cells (18, 19, 21), we find that ongoing IL-6 signaling is indispensable and foundational, acting upstream of IL-23 via its unique function to sustain RORt expression and thereby IL-23R expression.”
BackgroundTrans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells
Heink, S., Yogev, N., Garbers, C., Herwerth, M., Aly, L., Gasperi, C., Husterer, V., Croxford, A. L., Möller‐Hackbarth, K., Bartsch, H. S., et al. (2016) · Nature Immunology · doi:10.1038/ni.3632 · Cited by 401 · cited 1× · see citing works
“A additional form of IL-6 signaling, referred to as trans-presentation, involves binding of the cell suface-asscociated IL-6–sIL-6Ra complexes on a subset of dendritic cells to gp130 expressed on naive T cells, and has been proposed as a mechanism that promotes the development of pathogenic Th17 cells (41).”
BackgroundMatthews, V., Schuster, B., Schütze, S., Bussmeyer, I., Ludwig, A., Hundhausen, C., Sadowski, T., Saftig, P., Hartmann, D., Kallen, K.-J., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210584200 · Cited by 390 · see citing works
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The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice
Guo, B., Chang, E. Y., & Cheng, G. (2008) · Journal of Clinical Investigation · doi:10.1172/jci33342 · Cited by 372 · see citing works
Castell, J. V., Geiger, T. M., Groß, V., Andus, T., WALTER, E., Hirano, T., Kishimoto, T., & Heinrich, P. C. (1988) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1988.tb14383.x · Cited by 290 · cited 1× · see citing works
“While gp130 is ubiquitously expressed (33), IL-6Ra expression is restricted to hepatocytes (34) and subsets of leukocytes, including naïve T cells (35).”
BackgroundSaito, M., Yoshida, K., Hibi, M., Taga, T., & Kishimoto, T. (1992) · The Journal of Immunology · doi:10.4049/jimmunol.148.12.4066 · Cited by 282 · cited 1× · see citing works
“Whereas gp130 is ubiquitously expressed (33), IL-6R expression is restricted to hepatocytes (34) and subsets of leukocytes, including naïve T cells (35).”
BackgroundIL-6 rescues resting mouse T cells from apoptosis.
Teague, T., Marrack, P., Kappler, J., & Vella, A. (1997) · Journal of Immunology · doi:10.4049/jimmunol.158.12.5791 · Cited by 280 · cited 1× · see citing works
“IL-6 signaling promotes T cell proliferation and inhibits apoptosis via its actions to increase Bcl-2 (52).”
BackgroundMukasa, R., Balasubramani, A., Lee, Y. K., Whitley, S. K., Weaver, B. T., Shibata, Y., Crawford, G. E., Hatton, R. D., & Weaver, C. T. (2010) · Immunity · doi:10.1016/j.immuni.2010.04.016 · Cited by 273 · cited 14× · see citing works
“As IL-23 signaling via STAT4 is known to be a principal pathway mediating the transdifferentiation to Th1-like cells in vivo (19, 26), it is likely that the elevated expression of IL-23R by RORgt-transfected Il6ra Th17 cells contributed to the modest increase in expression of IFN-g by these cells compared to WT contro…”
BackgroundInfluentialSelf-citationKhanna, D., Denton, C. P., Lin, C. J. F., van Laar, J. M., Frech, T. M., Anderson, M. E., Baron, M., Chung, L., Fierlbeck, G., Lakshminarayanan, S., et al. (2018) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2017-211682 · Cited by 265 · cited 1× · see citing works
“In systemic Th17-related autoimmune diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, and systemic sclerosis, treatment with biologics that inhibit IL-6 is an effective or promising therapy (80-82).”
BackgroundA metalloprotease inhibitor blocks shedding of the IL-6 receptor and the p60 TNF receptor
Müllberg, J., Durie, F. H., Otten-Evans, C., Alderson, M. R., Rose‐John, S., Cosman, D. J., Black, R. A., & Mohler, K. M. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.155.11.5198 · Cited by 250 · cited 1× · see citing works
“In activated cells that express IL-6R, particularly activated neutrophils, monocytes, and T cells (36), the extracellular domain can be shed by proteolysis to liberate a functional soluble IL-6R (sIL-6R) (37, 38).”
BackgroundFujimoto, M., Serada, S., Mihara, M., Uchiyama, Y., Yoshida, H., Koike, N., Ohsugi, Y., Nishikawa, T., Ripley, B., Kimura, A., et al. (2008) · Arthritis & Rheumatism · doi:10.1002/art.24126 · Cited by 225 · see citing works
Genes coding for RNA polymerase β subunit in bacteria
Lisitsyn, N. A., MONASTYRSKAYA, G. S., & Sverdlov, E. D. (1988) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1988.tb14384.x · Cited by 217 · see citing works
Feng, T., Wang, L., Schoeb, T. R., Elson, C. O., & Cong, Y. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20092253 · Cited by 212 · cited 1× · see citing works
“Maintenance and pathogenesis of TH17 cells are dependent on ongoing IL-6 signaling Previous results using IL-6–deficient animals or blocking IL-6 interventions suggest that IL-6 is required to promote TH17-induced disease (12, 50, 51).”
BackgroundSelf-citationGarbers, C., Jänner, N., Chalaris, A., Moss, M. L., Floss, D. M., Meyer, D., Koch-Nolte, F., Rose-John, S., & Scheller, J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.229393 · Cited by 201 · cited 1× · see citing works
“IL-6R appears to be down-regulated primarily by cleavage of the extracellular domain by the metalloproteinases ADAM10 and ADAM17 in humans (73) or only ADAM 10 in mice (74), which would appear to favor a shift from classic to IL-6 transsignaling in developing TH17 cells.”
BackgroundJones, G. W., McLoughlin, R. M., Hammond, V. J., Parker, C. R., Williams, J. D., Malhotra, R., Scheller, J., Williams, A. S., Rose-John, S., Topley, N., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0901528 · Cited by 189 · cited 2× · see citing works
“IL-6 trans-signaling has been shown to affect the recruitment of Th17 cells in model of peritoneal inflammation (46), although it is unknown whether these effects were direct or indirect.”
BackgroundResultSelf-citationSoluble IL-6 receptor potentiates the antagonistic activity of soluble gp130 on IL-6 responses.
Müller-Newen, G., Küster, A., Hemmann, U., Keul, R., Horsten, U., Martens, A. S., Graeve, L., Wijdenes, J., & Heinrich, P. (1998) · Journal of Immunology · doi:10.4049/jimmunol.161.11.6347 · Cited by 186 · cited 1× · see citing works
“Given that gp130 is ubiquitously expressed, the local balance between IL-6–, sIL-6R–, and sgp130 IL-6–responsive target cells thus determines the prominent mode of IL-6 signaling acting on any cell type (40).”
BackgroundCutting Edge: Soluble IL-6R Is Produced by IL-6R Ectodomain Shedding in Activated CD4 T Cells
Briso, E. M., Dienz, O., & Rincón, M. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.11.7102 · Cited by 165 · cited 1× · see citing works
“In activated cells that express IL-6R, particularly activated neutrophils, monocytes, and T cells (36), the extracellular domain can be shed by proteolysis to liberate a functional soluble IL-6R (sIL-6R) (37, 38).”
BackgroundHirahara, K., Onodera, A., Villarino, A. V., Bonelli, M. M., Sciumè, G., Laurence, A. D. J., Sun, H., Brooks, S. R., Vahedi, G., Shih, H., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.04.014 · Cited by 157 · see citing works
Garbers, C., Monhasery, N., Aparicio-Siegmund, S., Lokau, J., Baran, P., Nowell, M. A., Jones, S. A., Rose-John, S., & Scheller, J. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.05.018 · Cited by 155 · cited 1× · see citing works
“The IL6RA variant rs2228145, which leads to increased proteolytic cleavage of IL-6R and, thus, a reduction in membranebound IL-6R in favor of increased serum levels (78), is associated with reduced risk of both RA (76) and IBD (77).”
BackgroundSelf-citationMultiple Sklerose: Neu entdeckter Signalmechanismus macht T-Zellen pathogen
(2017) · Fortschritte der Neurologie · Psychiatrie · doi:10.1055/s-0042-123476 · Cited by 155 · see citing works
Th memory for interleukin‐17 expression is stable in vivo
Lexberg, M. H., Taubner, A., Förster, A., Albrecht, I., Richter, A., Kamradt, T., Radbruch, A., & Chang, H. (2008) · European Journal of Immunology · doi:10.1002/eji.200838541 · Cited by 152 · see citing works
T cell-intrinsic role of IL-6 signaling in primary and memory responses
Nish, S. A., Schenten, D., Wunderlich, F. T., Pope, S. D., Gao, Y., Hoshi, N., Yu, S., Yan, X., Lee, H. K., Pasman, L., et al. (2014) · eLife · doi:10.7554/elife.01949 · Cited by 145 · see citing works
Interleukin-6 and soluble interleukin-6 receptor in the colonic mucosa of inflammatory bowel disease
Hosokawa, T., Kusugami, K., Ina, K., Ando, T., Shinoda, M., Imada, A., Ohsuga, M., Sakai, T., Matsuura, T., Ito, K., et al. (1999) · Journal of Gastroenterology and Hepatology · doi:10.1046/j.1440-1746.1999.01989.x · Cited by 112 · cited 1× · see citing works
“An excess of sIL6Ra, however, is a marker of active inflammation (43) and allows for trans-signaling to a wide variety of cell targets, and amplifies inflammatory responses through the recruitment and activation of mononuclear cells (44, 45).”
BackgroundTh17-cell plasticity in Helicobacter hepaticus–induced intestinal inflammation
Morrison, P., Bending, D., Fouser, L., Wright, J., Stockinger, B., Cooke, A., & Kullberg, M. (2013) · Mucosal Immunology · doi:10.1038/mi.2013.11 · Cited by 104 · see citing works
Oberg, H., Wesch, D., Grüssel, S., Rose‐John, S., & Kabelitz, D. (2006) · International Immunology · doi:10.1093/intimm/dxh396 · Cited by 102 · cited 1× · see citing works
“While gp130 is ubiquitously expressed (33), IL-6Ra expression is restricted to hepatocytes (34) and subsets of leukocytes, including naïve T cells (35).”
BackgroundTeague, T. K., Schaefer, B. C., Hildeman, D. A., Bender, J., Mitchell, T., Kappler, J. W., & Marrack, P. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.191.6.915 · Cited by 98 · cited 1× · see citing works
“IL-6 trans-signaling activates STAT1 and STAT3 in IL-6R–deficient TH17 cells ex vivo IL-6 signaling activates the transcription factors STAT3 and STAT1 in naïve CD4+ T cells, and studies have shown that CD4+ T cell activation status can alter the balance of STAT3/STAT1 activation downstream of IL-6 signaling (53, 54).”
BackgroundRegulated expression of gp130 and IL-6 receptor alpha chain in T cell maturation and activation.
Betz, U. (1998) · International Immunology · doi:10.1093/intimm/10.8.1175 · Cited by 70 · cited 2× · see citing works
“Collectively, these data show that both WT and Il6ra−/− CD4+ T cells are responsive to trans-signaling ex vivo, but this is limited by diminished gp130 expression, consistent with activation-induced down-regulation of gp130 in CD4+ T cells (53, 55, 56).”
BackgroundParisinos, C. A., Serghiou, S., Katsoulis, M., George, M. J., Patel, R. S., Hemingway, H., & Hingorani, A. D. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.05.022 · Cited by 67 · cited 9× · see citing works
“Expression of Il23r and other TH17-specific genes is required for several TH17-mediated diseases, including inflammatory bowel disease (IBD) (13–15), psoriasis (16), and ankylosing spondylitis (17), and exposure of TH17 cells to IL-23 is critical for TH17 maintenance and pathogenesis (15, 18–22).”
BackgroundInfluentialUpdating interleukin‐6 classic‐ and trans‐signaling
Scheller, J., Grötzinger, J., & Rose‐John, S. (2006) · Signal Transduction · doi:10.1002/sita.200600086 · Cited by 52 · cited 1× · see citing works
“, IL-1 and tumor necrosis factor– (TNF)] and innate sensing mechanisms contribute to the generation of IL-6, which elicits a broad range of biological functions on target cells (29).”
BackgroundPerona‐Wright, G., Kohlmeier, J. E., Bassity, E., Freitas, T. C., Mohrs, K., Cookenham, T. S., Situ, H., Pearce, E. J., Woodland, D. L., & Mohrs, M. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1119133109 · Cited by 41 · see citing works
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Kim, E., Paik, D., Ramírez, R. N., Biggs, D. G., Park, Y., Kwon, H., Choi, G. B., & Huh, J. R. (2021) · Immunity · doi:10.1016/j.immuni.2021.11.005 · Cited by 148 · see citing works
The Influence of Sex Hormones in Liver Function and Disease
Kasarinaite, A., Sinton, M. C., Saunders, P. T. K., & Hay, D. C. (2023) · Cells · doi:10.3390/cells12121604 · Cited by 134 · see citing works
Role of IL-6 in the commitment of T cell subsets
Korn, T., & Hiltensperger, M. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155654 · Cited by 125 · see citing works
Role of IL‐6 in dendritic cell functions
Xu, Y.-D., Cheng, M., Shang, P., & Yang, Y.-Q. (2021) · Journal of Leukocyte Biology · doi:10.1002/jlb.3mr0621-616rr · Cited by 93 · see citing works
Th17 Cells in Inflammatory Bowel Disease: Cytokines, Plasticity, and Therapies
Zhao, J., Lu, Q., Liu, Y., Shi, Z., Hu, L., Zeng, Z., Tu, Y., Xiao, Z., & Xu, Q. (2021) · Journal of Immunology Research · doi:10.1155/2021/8816041 · Cited by 126 · see citing works
“In inflammatory bowel disease, IL-6 produced by macrophages mediates apoptosis resistance and abnormal accumulation of T cells in the intestinal mucosa through its classical and trans-signals and promotes the differentiation of Th17 cells [34, 36].”
BackgroundThe deregulated immune reaction and cytokines release storm (CRS) in COVID-19 disease
Pasrija, R., & Naime, M. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.107225 · Cited by 109 · see citing works
“The IL-6 overproduction and infiltration of Th17 plays a key role in acute lung injury (ALI) causing ARDS.”
InfluentialThe Role of IL-17 Cytokines in Psoriasis
Mosca, M., Hong, J., Hadeler, E., Hakimi, M., Liao, W. J., & Bhutani, T. (2021) · ImmunoTargets and Therapy · doi:10.2147/itt.s240891 · Cited by 111 · see citing works
“inflammatory cytokines, including IL-6, which mediates Th17 commitment by naïve T cells.(41,42) IL-17 activates the”
BackgroundThe Role of IL-17 Cytokines in Psoriasis
Mosca, M., Hong, J. J., Hadeler, E. K., Hakimi, M., Liao, W. J., & Bhutani, T. (2021) · Dove Medical Press (Taylor and Francis Group) · Cited by 73 · see citing works
Binstadt, B. A., & Nigrovic, P. A. (2022) · Arthritis & Rheumatology · doi:10.1002/art.42137 · Cited by 69 · see citing works
Pollara, G., Turner, C. T., Rosenheim, J., Chandran, A., Bell, L. C. K., Khan, A., Patel, A. A., Peralta, L. F., Folino, A., Akarca, A. U., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abg7673 · Cited by 63 · see citing works
Systemic maternal inflammation promotes ASD via IL-6 and IFN-γ
Majerczyk, D., Ayad, E., Brewton, K. L., Saing, P., & Hart, P. C. (2022) · Bioscience Reports · doi:10.1042/bsr20220713 · Cited by 62 · see citing works
Th17 Cells and IL-17A in Ischemic Stroke
Wang, J., Gao, Y., Yuan, Y., Wang, H., Wang, Z., & Zhang, X. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03723-y · Cited by 53 · see citing works
LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation
Compton, S. E., Kitchen-Goosen, S. M., DeCamp, L. M., Lau, K. H., Mabvakure, B. M., Vos, M., Williams, K. S., Wong, K., Shi, X., Rothbart, S. B., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.04.017 · Cited by 47 · see citing works
IL-6 and diabetic kidney disease
Zhang, L., Xu, F., & Hou, L.-Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1465625 · Cited by 50 · see citing works
The nutritional roles of zinc for immune system and COVID-19 patients
Jin, D., Wei, X., He, Y., Zhong, L., Lü, H., Lan, J., Wei, Y., Liu, Z., & Liu, H. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1385591 · Cited by 46 · see citing works
Parekh, K., Hariharan, K., Qu, Z., et al. (2021) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2021.121079 · Cited by 46 · see citing works
Structure of the IL-27 quaternary receptor signaling complex
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Kim, S. T., Sheshadri, A., Shannon, V. R., Kontoyiannis, D. P., Kantarjian, H. M., Garcia‐Manero, G., Ravandi, F., Im, J. S., Boddu, P. C., Bashoura, L., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.590494 · Cited by 43 · see citing works
“Although not statistically significant, the levels of soluble IFNg, as well as IL-6 and IL-17A, key cytokines for Th17 cell differentiation, plasticity, and function (10, 16), in the BAL fluid were higher in the ICI group than in the control group (Figure 3H).”
BackgroundDiabetic complications and prospective immunotherapy
Reynolds, L., Luo, Z., & Singh, K. N. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1219598 · Cited by 41 · see citing works
New insights into the endotypes of chronic rhinosinusitis in the biologic era
Wang, M., Li, Y. C., Li, J., et al. (2025) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2025.02.015 · Cited by 39 · see citing works
The Role of IL-17A in Mediating Inflammatory Responses and Progression of Neurodegenerative Diseases
Zheng, M., & Luo, L. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26062505 · Cited by 43 · see citing works
“In the initial stage, the binding of TGF-β , IL-6, or IL-21 to their respective receptors triggers the differentiation of naïve CD4 + T cells into Th17 precursor cells, with IL-6 playing a central role [37].”
How could we forget immunometabolism in SARS-CoV2 infection or COVID-19?
Kumar, V. (2020) · International Reviews of Immunology · doi:10.1080/08830185.2020.1840567 · Cited by 39 · see citing works
“The increased number of Th17 cells in the lungs of severe COVID-19 patients may be induced by the increase in the pulmonary IL-6 levels via signal transducer and activator of transcription 3 (STAT3) that induces the programing of Th17-related genes for Th17 cell development (Figure 2B) [60].”
BackgroundCheng, H., Nan, F., Ji, N., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-62628-7 · Cited by 38 · see citing works
“Although IL-21 can somewhat replace IL-6 and synergistically drive Th17 differentiation together with TGF-β 72 , IL-6 plus TGF-β are still considered to be essential for the maintenance of Th17 in both unin fl amed and in fl amed intestine 45,73 .”
Batf stabilizes Th17 cell development via impaired Stat5 recruitment of Ets1‐Runx1 complexes
Pham, D., Silberger, D. J., Nguyen, K. N., Gao, M., Weaver, C., & Hatton, R. D. (2023) · EMBO Journal · doi:10.15252/embj.2021109803 · Cited by 25 · see citing works
“Studies by this lab and others have established that Th17 cells are highly plastic and that without sustained IL-6 and TGF-β signaling, acquire a Th1-like signature, similar to what was observed in Batf-deficient Th17 cells (Lexberg et al, 2008; Lee et al, 2009; Harbour et al, 2020; Fig 1A–”
BackgroundResultInfluentialSelf-citationWang, X., Ni, T., Miao, J., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102643 · Cited by 32 · see citing works
Tackling Inflammatory Bowel Diseases: Targeting Proinflammatory Cytokines and Lymphocyte Homing
Song, Y., Yuan, M., Xu, Y., & Xu, H. (2022) · Pharmaceuticals · doi:10.3390/ph15091080 · Cited by 30 · see citing works
“IL-6 mediates the proliferation of TH17 cells in concert with TGF-β by affecting signal transducers and activators of transcription (STAT3), which is essential for TH17 cell maintenance and function [59].”
BackgroundArellano, G., Loda, E., Chen, Y., Neef, T., Cogswell, A. C., Primer, G., Joy, G., Kaschke, K., Wills, S., Podojil, J. R., et al. (2023) · Brain · doi:10.1093/brain/awad373 · Cited by 29 · see citing works
Impact of interleukin-6 on T cells in kidney transplant recipients
Chandran, S., & Tang, Q. (2022) · American Journal of Transplantation · doi:10.1111/ajt.17209 · Cited by 25 · see citing works
Luo, Y., Shreeder, B., Jenkins, J. W., Shi, H., Lamichhane, P., Zhou, K., Bahr, D. A., Kurian, S., Jones, K. A., Daum, J. I., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-007661 · Cited by 25 · see citing works
Seyedi, D., Espandar, N., Hojatizadeh, M., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1486476 · Cited by 25 · see citing works
Unravelling the broader complexity of IL-6 involvement in health and disease
Jenkins, R. L., Hughes, S. T. O., Figueras, A. C., & Jones, S. A. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155684 · Cited by 25 · see citing works
“While Il6ra -/- and Il6 -/- mice are viable 50-52 , these mice show differences in wound healing, susceptibility to colitis and alterations in glucose tolerance 22,53-55 .”
BackgroundSelf-citationDi, Y., Song, Y., Xu, K.-J., Wang, Q., Zhang, L., Liu, Q., Zhang, M., Liu, X.-B., & Wang, Y.-T. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.3c08363 · Cited by 21 · see citing works
STAT5 Represses a STAT3-Independent Th17-like Program during Th9 Cell Differentiation
Canaria, D. A., Yan, B., Clare, M. G., Zhang, Z., Taylor, G. A., Boone, D. L., Kazemian, M., & Olson, M. R. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2100165 · Cited by 24 · see citing works
PIM kinases regulate early human Th17 cell differentiation
Buchacher, T., Shetty, A., Koskela, S. A., Smolander, J., Kaukonen, R., Sousa, A. G. G., Junttila, S., Laiho, A., Rundquist, O., Lönnberg, T., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113469 · Cited by 21 · see citing works
The Role of gp130 Cytokines in Tuberculosis
Ritter, K., Rousseau, J., & Hölscher, C. (2020) · Cells · doi:10.3390/cells9122695 · Cited by 24 · see citing works
Peng, S., Shen, L., Tian, M., Li, H., & Wang, S. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.9566 · Cited by 21 · see citing works
Use of Immune Checkpoint Inhibitors in Cancer Patients with Pre-Existing Sarcoidosis
Kim, S. T., Pundole, X., Dadu, R., Lambotte, O., Ramos‐Casals, M., & Suarez-Almazor, M. E. (2021) · Immunotherapy · doi:10.2217/imt-2020-0272 · Cited by 20 · see citing works
“Serum IFN-γ, a key effector cytokine of Th1 cells and serum IL-6, a critical cytokine of Th17 cell differentiation, maintenance and plasticity [32], were well correlated in our patient with sarcoidosis disease activity, suggesting that like classical sarcoidosis and potentially de novo sarcoidosis-irAE, Th1 and Th17.”
BackgroundYan, S., Golumba-Nagy, V., Kotschenreuther, K., Thiele, J., Refaian, N., Deng, S., Gloyer, L., Dittrich-Salamon, M., Meyer, A., Heindl, L. M., et al. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-04076-2 · Cited by 21 · see citing works
Antigen-presenting cells as arbiters of mucosal tolerance and immunity
Hölting, T. L. B., Park, T., & Brown, C. C. (2025) · Nature Immunology · doi:10.1038/s41590-025-02320-6 · Cited by 18 · see citing works
“IL-6 and TGFβ promote initial T H 17 lineage commitment, but IL-23 and IL-6 are critically required for their maintenance 93,94 .”
InfluentialCOVID-19, what could sepsis, severe acute pancreatitis, gender differences, and aging teach us?
Gallo, C. G., Fiorino, S., Posabella, G., Antonacci, D., Tropeano, A., Pausini, E., Pausini, C., Guarniero, T., Hong, W., Giampieri, E., et al. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155628 · Cited by 17 · see citing works
Periodontitis and COVID-19: Immunological Characteristics, Related Pathways, and Association
Qi, M., Sun, W., Wang, K., Li, W., Lin, J., Gong, J., & Wang, L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24033012 · Cited by 21 · see citing works
“Both the induction and maintenance of TH17 cells depend on IL-6 signaling [84].”
BackgroundIL-17 is Associated with Disease Severity and Targetable Inflammatory Processes in Heart Failure
Baumhove, L., van Essen, B. J., Dokter, M. M., et al. (2024) · ESC Heart Failure · doi:10.1002/ehf2.14968 · Cited by 18 · see citing works
IL-2, IL-6 and chitinase 3-like 2 might predict early relapse activity in multiple sclerosis
Petržalka, M., Meluzínová, E., Libertínová, J., Mojžišová, H., Hanzalová, J., Ročková, P., Elišák, M., Kmetonyová, S., Šanda, J., Sobek, O., et al. (2022) · PLoS ONE · doi:10.1371/journal.pone.0270607 · Cited by 16 · see citing works
Cao, L., Deng, J., Chen, W., He, M., Zhao, N., Huang, H., Ling, L., Li, Q., Zhu, X., & Wang, L. (2023) · Journal of Clinical Investigation · doi:10.1172/jci168384 · Cited by 18 · see citing works
“In addition to having a key role in Th17 cell induction, IL-6 is necessary for retaining the transcriptional and functional identities of Th17 (7), which is indispensable for EAE disease progression.”
Th17 cells: A new target in kidney disease research
Zhang, T., Huo, H., Zhang, Y., Tao, J., Yang, J., Rong, X., & Yang, Y. (2024) · International Reviews of Immunology · doi:10.1080/08830185.2024.2321901 · Cited by 18 · see citing works
Audu, C. O., Wolf, S., Joshi, A., Moon, J. Y., Melvin, W. J., Sharma, S. B., Davis, F. M., Obi, A. T., Wasikowski, R., Tsoi, L. C., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.172959 · Cited by 17 · see citing works
Xie, Y., Chai, M., Xing, Y., Zhou, P., Wei, P., & Hua, H. (2025) · Journal of Nanobiotechnology · doi:10.1186/s12951-025-03308-y · Cited by 16 · see citing works
“IL-6 is essential for maintaining the transcriptional and functional identity of Th17 cells through continuous classical receptor signaling, thus promoting inflammatory responses in SS [79].”
Targeting inerleukin-6 for renoprotection
Gubernatorova, E. O., MIu, S., Drutskaya, M. S., Lebedeva, S. A., Bukhanova, D., Materenchuk, M. Y., & Mutig, K. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1502299 · Cited by 14 · see citing works
Huang, Y., Ba, X., Wang, H., et al. (2023) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.13880 · Cited by 14 · see citing works
“TP treatment significantly decreased the arthritis score, alleviated cartilage and bone destruction, and downregulated the levels of serum anti-CII IgG1 antibody, TNF-α, and IL-6.”
BackgroundInfluentialPark, J. S., & Perl, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310749 · Cited by 14 · see citing works
“IL-6 signaling induces Th17-related gene expression via the signal transducer and activator of transcription (STAT)3 [268].”
BackgroundTREM-2 Drives Development of Multiple Sclerosis by Promoting Pathogenic Th17 Polarization
Qu, S., Hu, S., Xu, H., Wu, Y., Ming, S., Zhan, X., Wang, C., & Huang, X. (2023) · Neuroscience Bulletin · doi:10.1007/s12264-023-01094-x · Cited by 14 · see citing works
“IL-6 synergizes with interleukin-6 receptor (IL-6R) to regulate Th17 cell differentiation and to maintain cytokine expression in effector Th17 cells [15].”
Effects of methylglyoxal on intestine and microbiome composition in aged mice
Tirelli, E., Pucci, M., Squillario, M., Bignotti, G., Messali, S., Zini, S., Bugatti, M., Cadei, M., Memo, M., Caruso, A., et al. (2025) · Food and Chemical Toxicology · doi:10.1016/j.fct.2025.115276 · Cited by 13 · see citing works
Simmalee, K., Kawamatawong, T., Vitte, J., et al. (2025) · Frontiers in Medicine · doi:10.3389/fmed.2025.1514846 · Cited by 13 · see citing works
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“Th1/Th17 cells release IL-6, IL-17, etc., which are essential for cell signalling in the inflammation cascade [64].”
Immune responses in COVID-19 patients: Insights into cytokine storms and adaptive immunity kinetics
Zhang, J.-G. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e34577 · Cited by 13 · see citing works
“Additionally, IL-6, in conjunction with IL-23 and TNF-α , promote the differentiation of naive Th cells into Th17 cells [48], which secrete the potent pro-inflammatory cytokine IL-17, observed in abundance in COVID-19.”
BackgroundTakayasu arteritis: a geographically distant but immunologically proximal MHC-I-opathy
Abacar, K., Macleod, T., Di̇reskeneli̇, H., et al. (2025) · The Lancet Rheumatology · doi:10.1016/s2665-9913(24)00307-2 · Cited by 12 · see citing works
Ma, S., Lu, Y., Sui, S., Yang, J.-S., Fu, B., Tan, P.-X., Chai, Y., Lv, J., Kong, L., Wu, X., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1572821 · Cited by 13 · see citing works
“TNF-a , working together with IL-6, enhances Th17 cell polarization, worsening the immune in fl ammatory condition (27).”
Yu, Z., Xu, Z., Fu, T., Liu, S., Cui, J., Zhang, B., Liang, J., Pang, C., Ke, Y., Wang, R., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-58094-w · Cited by 13 · see citing works
Kim, S. T., Tayar, J. H., Fu, S., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-002716 · Cited by 11 · see citing works
Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis.
Pilipović, I., Stojić-Vukanić, Z., & Leposavić, G. (2023) · Pharmacology and Therapeutics · doi:10.1016/j.pharmthera.2023.108358 · Cited by 12 · see citing works
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Shao, A., Zhao, Q., & Chen, M. (2024) · Digestive Diseases and Sciences · doi:10.1007/s10620-024-08588-2 · Cited by 11 · see citing works
“During the inflammatory state, CD4 + T cells differentiate into Th17 effector cells in response to IL-6 and TGF-β secreted by macrophages [9].”
BackgroundUmbilical Cord Mesenchymal Stromal/Stem Cells and Their Interplay with Th-17 Cell Response Pathway
Najar, M., Rahmani, S., Faour, W. H., Alsabri, S. G., Lombard, C. A., Fayyad‐Kazan, H., Sokal, E. M., Merimi, M., & Fahmi, H. (2024) · Cells · doi:10.3390/cells13020169 · Cited by 9 · see citing works
Jiang, Q., Chi, X., Wei, T., Nakayamada, S., Yu, S., Sun, Y., Zhao, X., Zhou, J., Fan, Y. L., Gu, J., et al. (2024) · Journal of Autoimmunity · doi:10.1016/j.jaut.2024.103304 · Cited by 9 · see citing works
Roy, Z. A. V., Kak, G., Fallet, R. W., et al. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03376-9 · Cited by 9 · see citing works
Inflammatory Pathways in Sarcoidosis
Barna, B. P., Judson, M. A., & Thomassen, M. J. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-68748-9_3 · Cited by 9 · see citing works
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): diagnosis and management
Fan, J., Jiao, J., Chang, H.-Q., Zhong, D., Liu, X.-B., Li, J., Chen, L., Jin, R., & Wu, X. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07506-y · Cited by 11 · see citing works
Liu, R., Mao, Y., Gu, Z.-Y., et al. (2021) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2021/7671247 · Cited by 8 · see citing works
“Furthermore, IL-6 receptor signaling regulates the expression of117-related genes by activating STAT3 to induce the development of 117 cells [49].”
BackgroundMillrine, D., Figueras, A. C., Fernandez, J. U., Andrews, R., Szomolay, B., Cossins, B. C., Rice, C. M., Li, J., Tyrrell, V. J., McLeod, L., et al. (2023) · The Journal of Immunology · doi:10.4049/jimmunol.2300114 · Cited by 9 · see citing works
Self-citationBracken, S. J., Suthers, A. N., DiCioccio, R. A., Su, H., Anand, S. M., Poe, J. C., Jia, W., Visentin, J., Basher, F., Jordan, C. Z., et al. (2023) · Blood Advances · doi:10.1182/bloodadvances.2023010362 · Cited by 8 · see citing works
Yuan, H., Zheng, P., Zhang, M., Li, H., Lu, K., Yang, C., Li, M., & Liu, S. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107525 · Cited by 6 · see citing works
Qiu, D., Yan, B., Xue, H., Xu, Z., Tan, G., & Liu, Y. (2025) · Experimental Cell Research · doi:10.1016/j.yexcr.2025.114457 · Cited by 5 · see citing works
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Li, D., Tao, H., Tan, X., Ling, H., Lu, Y., Zhang, H., Theany, S., & Xu, H. (2025) · Frontiers in Microbiology · doi:10.3389/fmicb.2025.1643209 · Cited by 5 · see citing works
STAT3 haploinsufficiency is associated with autosomal dominant hyper-IgE syndrome
Andreani, V., Forde, A. J., Fliegauf, M., Bressan, G., Noé, V., Ott, N., Saghafi, S., Vornholz, L., Isay, S. E., Ruland, J., et al. (2025) · Science Advances · doi:10.1126/sciadv.adw2464 · Cited by 8 · see citing works
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Contextualizing TH17 cells in cancer
Pang, D., Bertocchi, A., Powrie, F. M., & Pohin, M. (2026) · Nature reviews. Immunology · doi:10.1038/s41577-025-01250-6 · Cited by 6 · see citing works
Synergizing adaptive immunity and regenerative signals to enhance osteochondral defects repair
Lin, C., Ying, C., Xu, Y., Zou, Y., Chen, R., Xu, K., Ji, X., Cao, Q., Weng, J., Jiang, L., et al. (2024) · Bioactive Materials · doi:10.1016/j.bioactmat.2024.12.011 · Cited by 5 · see citing works
“The differentiation of Th17 cells is a multifaceted process modulated by a constellation of cytokines, with IL-6 playing an indispensable role in the maintenance and functional integrity of Th17 cells [25].”
Martín‐Hernández, D., Gutiérrez, I. L., González‐Prieto, M., MacDowell, K. S., Robledo‐Montaña, J., Tendilla‐Beltrán, H., Calleja-Rodríguez, N., Bris, Á. G., Ulecia-Morón, C., Moreno, B., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-08011-8 · Cited by 5 · see citing works
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Brede, K.-M., Schmid, J., Steinmetz, O. M., et al. (2021) · Immunology Letters · doi:10.1016/j.imlet.2021.05.002 · Cited by 5 · see citing works
PROCR diminishes the efficacy of radiation by impairing T-cell-mediated antitumour immunity
Chen, W., Zhang, C., Li, Z., Xu, Z., Ding, C., Wu, J., Wei, H., Deng, Z., He, T., Long, L., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-62558-4 · Cited by 4 · see citing works
“…the other hand, although IL-6 has been shown to play an important role in inducing Th17 differentiation andinhibitingTregdifferentiationandfunction 50 – 52 ,giventhecomplex composition of T-cell subpopulations in the tumour microenvironment, the relationshipbetween IL-6and antitumour immunity…”
Townsend, K., Kannambath, S., Hayman, G., Döffinger, R., Ceron‐Gutierrez, L., Ebrahimi, S., Pavlova, V., Gothard, P., Brown, M., Tahami, F., et al. (2025) · Clinical & Experimental Immunology · doi:10.1093/cei/uxaf053 · Cited by 4 · see citing works
Bradl, M., Yu, Q., & Takai, Y. (2025) · Seminars in Immunology · doi:10.1016/j.smim.2025.101945 · Cited by 4 · see citing works
Decreased expression of P-glycoprotein in the placenta of women with autoimmune disease
Pollinzi, A., Mirdamadi, K., Karimianpour, N., et al. (2024) · Drug Metabolism and Disposition · doi:10.1016/j.dmd.2024.100031 · Cited by 4 · see citing works
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Fortmann, S. D., Frey, B. F., Hanumanthu, V. S., Liu, S., Goldsborough, A. S., Kilchrist, K. V., Ferrell, P. B., Weaver, C. T., Grant, M. B., & Welner, R. S. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.13.528370 · Cited by 4 · see citing works
“2023 13 February 2023 16 from the culture media, an essential component of Th17 maintenance (Harbour et al., 2020).”
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Early-life viral infections and asthma: new cells and ideas
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“Additionally, the presence of pro-inflammatory cytokines like IL-6 and IL-23 favors Th17 polarization [78], whereas deficiencies in TGF-β and IL-2 limit Treg maintenance [79, ].”
The role of interleukin-6 in diabetic retinal disease: pathophysiology and therapeutic targeting
Harlow, R. E. A., Rose‐John, S., Hašková, Z., Fauser, S., & Mesquida, M. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1805665 · Cited by 4 · see citing works
“The close cell-to-cell contact in trans-presentation ensures signaling is restricted to adjacent target cells and prevents widespread and uncontrolled activation (98).”
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“This IL-6, in turn, not only promotes its own transcription via STAT3 but, more importantly, serves as a critical signal for driving both the afore-mentioned Th17 cell differentiation and the terminal differentiation of B cells into antibody-secreting plasma cells [67, 68].”
Prenatal antibiotics exposure does not influence experimental allergic asthma in mice
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Inflammatory bowel disease pathogenesis mediated by Th17 cells: cytokines, microbiota, and therapies
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“Recent work has established that IL-6 has an important function in maintenance of these cells [33, 34].”
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- Authors
- Harbour, S. N., DiToro, D. F., Witte, S. J., Zindl, C. L., Gao, M., Schoeb, T. R., Jones, G. W., Jones, S. A., Hatton, R. D., & Weaver, C. T.
- Affiliations
- University of Alabama at Birmingham (US)
- University of Bristol (GB)
- Cardiff University (GB)
- Corresponding author
- Weaver, Casey T.
- ORCID
- Venue
- Science Immunology
- Published
- 2020-07-03
- Volume
- 5
- Issue
- 49
- ISSN
- 2470-9468 (ISSN-L)
- PMC
- PMC7843024
- OpenAlex
- W3043211816
- Semantic Scholar
- 45e487591763410f37c7b80c25d0b675ce81d427
- Cited by
- 151
- References
- 98
- Citations by year
- 2026: 27 · 2025: 37 · 2024: 25 · 2023: 25 · 2022: 13 · 2021: 20 · 2020: 4
- FWCI
- 4.48
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- Locations
- Science Immunology (publishedVersion)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion, other-oa)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Bristol Research (University of Bristol) (submittedVersion, other-oa)
- PubMed Central (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- Wellcome (079044)
- Versus Arthritis (19796 20770, 20305)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- Th17 cells, IL-6 receptor signaling, RORγt, IL-23, T cell differentiation, cytokine signaling
- MeSH terms
- Animals, Colitis, Colon, Female, Male, Mice, Inbred C57BL, Transcription, Genetic, Signal Transduction, Interleukin-6, Mice, Knockout, Receptors, Interleukin-6, Th17 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-23.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-23.
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