IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state
Abstract
IL-17-producing Th (Th17) comprise a distinct lineage of pro-inflammatory Th that are major contributors to autoimmune diseases. Treatment with IL-6 and transforming growth factor beta (TGFbeta) induces naive CD4+ T cells to generate Th17, which also requires expression of the IL-6/TGFbeta target RORgammat. We reported that IL-6 transduces two signaling pathways via tyrosine redidues of the signal transducer gp130: one depends on signal transducers and activators of transcription (STAT)-3 activation and the other on Src homology region 2 domain-containing phosphatase 2 (SHP2)/Grb2 associated binder (Gab)/mitogen-activated protein kinase (MAPK) activation. Here, we showed that CD4+ T cells carrying a mutant gp130 that transduces the SHP2/Gab/MAPK pathway but not the STAT3-mediated one failed to develop into Th17, while CD4+ T cells whose mutant gp130 transduces the STAT3 signal only generated Th17, indicating that IL-6 acts directly on T cells through the tyrosine residues of gp130 required for STAT3 activation to promote the development of Th17. Moreover, we found that gp130-STAT3 pathway is essential for Th17 development and for the expression of RORgammat by using T cells specifically lacking gp130 and STAT3. Noteworthy is that the regulatory T cell (Treg) percentages and numbers were comparable between all mutant mice we tested in vivo, although we showed that IL-6-gp130-STAT3 pathway suppressed Treg development in vitro. Thus, we conclude that IL-6 acts directly to promote the development of Th17 by activating the T cell gp130-STAT3 pathway but has a minimum effect on Treg development at least in the steady state in vivo. Therefore, blockade of IL-6-gp130-STAT3 pathway in CD4+ T cells could be a good target for controlling unwanted Th17-mediated immune responses including autoimmune diseases.
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STAT3 activated by IL-6, IL-21, and IL-23 upregulates RORγt, RORα, IL-21, IL-23R, and IL-17, helping development and stabilization of Th17 cells.
“STAT3 activated by several proinflammatory cytokines, e.g., IL-6, IL-21, and IL-23, upregulates RORγt, RORα, IL-21, IL-23R, and IL-17, thereby helping in the development and stabilization of Th17 cells”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Nishihara et al., 2007
The Introduction and the section on gp130 STAT3-binding residues report that IL-6–gp130–STAT3 signaling promotes RORγt expression and Th17 development. The latter section only suggests that STAT3 might induce IL-17 mRNA; our copy does not establish the claimed STAT3-mediated upregulation of RORα, IL-21, or IL-23R, activation by IL-21 or IL-23, or stabilization of Th17 cells. Page numbers were not provided. (LLM, conf=0.88)
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“STAT3 activated by several proinflammatory cytokines, e.g., IL-6, IL-21, and IL-23, upregulates RORgt, RORa, IL-21, IL-23R, and IL-17, thereby helping in the development and stabilization of Th17 cells (Laurence et al., 2007; Nishihara et al., 2007; Yang et al., 2007b, 2008b; Zhou et al., 2007).”
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- Authors
- Nishihara, M., Ogura, H., Ueda, N., Tsuruoka, M., Kitabayashi, C., Tsuji, F., Aono, H., Ishihara, K., Huseby, E., Betz, U. A. K., Murakami, M., & Hirano, T.
- Affiliations
- The University of Osaka (JP)
- Santen (Japan) (JP)
- University of Massachusetts Chan Medical School (US)
- Merck KGaA, Darmstadt (Germany) (DE)
- RIKEN (JP)
- ORCID
- Venue
- International Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-05-09
- Volume
- 19
- Issue
- 6
- Pages
- 695-702
- ISSN
- 0953-8178 (ISSN-L)
- 1460-2377
- OpenAlex
- W2159451122
- Cited by
- 268
- References
- 8
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 15 · 2023: 5 · 2022: 15 · 2021: 6 · 2020: 11 · 2019: 12 · 2018: 17 · 2017: 15 · 2016: 9 · 2015: 17 · 2014: 10 · 2013: 24 · 2012: 12
- FWCI
- 6.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- interleukin-6, gp130, STAT3, Th17 cells, regulatory T cells, CD4+ T cells, RORγ, TGF-beta, IL-6 signaling, autoimmune disease, T cell differentiation
- MeSH terms
- Animals, Arthritis, Experimental, Cell Count, Cell Differentiation, Flow Cytometry, T-Lymphocytes, Helper-Inducer, Lymph Nodes, Lymphocyte Activation, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Receptors, Thyroid Hormone, Spleen, Signal Transduction, CD4-Positive T-Lymphocytes, Interleukin-6, Receptors, Retinoic Acid, Mice, Knockout, Interleukin-17, T-Lymphocytes, Regulatory, STAT3 Transcription Factor, Cytokine Receptor gp130, Mice, Forkhead Transcription Factors, Nuclear Receptor Subfamily 1, Group F, Member 3
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