Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5

Xiang Ping Yang; Kamran Ghoreschi; Scott M. Steward-Tharp; Jaime Rodriguez-Canales; Jinfang Zhu; John R. Grainger; Kiyoshi Hirahara; Hong Wei Sun; Lai Wei; Golnaz Vahedi; Yuka Kanno; John J. O'Shea; Arian Laurence

doi:10.1038/ni.1995

Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5

Xiang Ping Yang, Kamran Ghoreschi, Scott M. Steward-Tharp, Jaime Rodriguez-Canales, Jinfang Zhu, John R. Grainger, Kiyoshi Hirahara, Hong Wei Sun, Lai Wei, Golnaz Vahedi, Yuka Kanno, John J. O'Shea, Arian Laurence

Translational Molecular Pathology

Research output: Contribution to journal › Article › peer-review

481 Scopus citations

Abstract

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_H17 cell) subset. Thus, the balance rather than the absolute magnitude of these signals determined the propensity of cells to make a key inflammatory cytokine.

Original language	English (US)
Pages (from-to)	247-254
Number of pages	8
Journal	Nature Immunology
Volume	12
Issue number	3
DOIs	https://doi.org/10.1038/ni.1995
State	Published - Mar 2011

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1038/ni.1995

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title = "Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5",

abstract = "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.",

author = "Yang, {Xiang Ping} and Kamran Ghoreschi and Steward-Tharp, {Scott M.} and Jaime Rodriguez-Canales and Jinfang Zhu and Grainger, {John R.} and Kiyoshi Hirahara and Sun, {Hong Wei} and Lai Wei and Golnaz Vahedi and Yuka Kanno and O'Shea, {John J.} and Arian Laurence",

note = "Funding Information: We thank J. Simone, J. Lay and the National Institute of Arthritis, Musculoskeletal and Skin Diseases Laboratory Animal Care and Use Section staff for technical support; D. Levy (New York University) for mice with loxP-flanked Stat3 alleles; C. Dong (MD Anderson) for IL-17F–RFP reporter mice; W. Ouyang (Genentech) for monoclonal anti-IL-22; and S. Kuchen, F.C. Eberle and K. Tarbell for comments on the manuscript. Supported by the Intramural Research programs of National Institute of Arthritis, Musculoskeletal and Skin Diseases and National Institute of Allergy and Infectious Diseases.",

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AU - Yang, Xiang Ping

AU - Ghoreschi, Kamran

AU - Steward-Tharp, Scott M.

AU - Rodriguez-Canales, Jaime

AU - Zhu, Jinfang

AU - Grainger, John R.

AU - Hirahara, Kiyoshi

AU - Sun, Hong Wei

AU - Wei, Lai

AU - Vahedi, Golnaz

AU - Kanno, Yuka

AU - O'Shea, John J.

AU - Laurence, Arian

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N2 - 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.

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Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5

Abstract

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