Opposing regulation of the Il17 locus through direct, reciprocal actions of STAT3 and STAT5

By Xiang-Ping Yang, K. Ghoreschi, Scott M. Steward-Tharp, J. Rodriguez-Canales, Jinfang Zhu, J. Grainger, K. Hirahara, Hong-Wei Sun, Lai Wei, G. Vahedi and 3 more. Nature Immunology, 2011

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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 (TH17 cell) subset. Thus, the balance rather than the absolute magnitude of these signals determined the propensity of cells to make a key inflammatory cytokine.

Subfields: Immunology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/a3685d6e173895416a2f31868b9b1a22abe2801c

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In Immunology

In Pathology and Forensic Medicine

T. Hirano

Citations in the corpus

Interleukin-2 at the Crossroads of Effector Responses, Tolerance, and Immunotherapy (2013, unknown): “It has beenproposed that IL-2-activated STAT5 competes with STAT3 for binding to sites in the Il17a locus, thus inhibiting Il17a transcription (Yang et al., 2011), but direct STAT5 inhibition of Il17a transcription has not been shown.”
IL-2 Family Cytokines: New Insights into the Complex Roles of IL-2 as a Broad Regulator of T helper Cell Differentiation (2011, background): “Because IL-6 signals via STAT3 and IL-2 via STAT5, it was proposed that IL-2-induced STAT5 competed for STAT3 binding sites in the Il17a gene locus, inhibiting Il17a transcription [48], although direct inhibition of Il17a transcription by STAT5 was not shown.”
JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. (2012, background): “In this case, the actions of STAT5A and STAT5B are very direct as they compete with STAT3 binding to the Il17a-f locus (Yang et al., 2011).”
Regulation of the immune response by the aryl hydrocarbon receptor (2018, background): “IL-2 has been shown to inhibit Th17 cell differentiation (Chen et al., 2011; Laurence et al., 2007; Yang et al., 2011).”
Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550) (2011, background): “more complex (68), the expression of IL-23R and IL-22 are strictly dependent on STAT3 activation (51).”
IL-6 in inflammation, autoimmunity and cancer (2020, background): “Furthermore, opposing regulation of the locus encoding IL-17 through the reciprocal actions of STAT3 and STAT5 suggest the balance between IL-6–STAT3 and IL-2–STAT5 regulates the development of T h 17 cells and T reg cells from naive CD4(+)T cells (189).”