Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5
Open accessAbstract
Interleukin 2 (IL-2), a cytokine linked to human autoimmune disease, limits IL-17 production. Here we found that deletion of the gene encoding the transcription factor STAT3 in T cells abrogated IL-17 production and attenuated autoimmunity associated with IL-2 deficiency. Whereas STAT3 induced IL-17 and the transcription factor RORγt and inhibited the transcription factor Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and RORγt. STAT3 and STAT5 bound to multiple common sites across the locus encoding IL-17. The induction of STAT5 binding by IL-2 was associated with less binding of STAT3 at these sites and the inhibition of associated active epigenetic marks. 'Titration' of the relative activation of STAT3 and STAT5 modulated the specification of cells to the IL-17-producing helper T cell (T(H)17 cell) subset. Thus, the balance rather than the absolute magnitude of these signals determined the propensity of cells to make a key inflammatory cytokine.
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The results suggest a model in which Tsc22d3 acts as a transcriptional repressor that competes with Th17-positive regulators for binding sites.
“This suggests a model where Tsc22d3 exerts its Th17-negative function as a transcriptional repressor that competes with Th17 positive regulators over binding sites, analogous to previous findings in CD4+ regulation29,43.”
From Dynamic regulatory network controlling TH17 cell differentiation (2013) · cites this paper as [43]
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References 50 · Cited by 583
- Authors
- Yang, 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., Kanno, Y., O'Shea, J. J., & Laurence, A.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Laurence, Arian
- ORCID
- Venue
- Nature Immunology
- Published
- 2011-01-30
- Volume
- 12
- Issue
- 3
- Pages
- 247-254
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC3182404
- OpenAlex
- W1982696151
- Cited by
- 583
- References
- 50
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 17 · 2023: 24 · 2022: 29 · 2021: 36 · 2020: 32 · 2019: 35 · 2018: 35 · 2017: 41 · 2016: 39 · 2015: 51 · 2014: 50 · 2013: 62 · 2012: 62
- FWCI
- 29.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 AR999999)
- National Institute of Allergy and Infectious Diseases (ZIAAI001169)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (Z01AR041159)
- 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
- IL-17, STAT3, STAT5, interleukin-2, Th17 cells, Foxp3, RORγt, epigenetic regulation, autoimmunity, T cell differentiation, cytokine regulation
- MeSH terms
- Animals, Cell Differentiation, Flow Cytometry, Gene Expression Regulation, Humans, Interleukin-2, Mice, Inbred C57BL, T-Lymphocytes, Immunoblotting, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Interleukin-17, STAT3 Transcription Factor, STAT5 Transcription Factor, Mice, Genetic Loci
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