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Citations to this article

Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice
Partha S. Biswas, … , Govind Bhagat, Alessandra B. Pernis
Partha S. Biswas, … , Govind Bhagat, Alessandra B. Pernis
Published August 9, 2010
Citation Information: J Clin Invest. 2010;120(9):3280-3295. https://doi.org/10.1172/JCI42856.
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Research Article Autoimmunity Article has an altmetric score of 6

Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice

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Abstract

Deregulated production of IL-17 and IL-21 plays a key pathogenic role in many autoimmune disorders. A delineation of the mechanisms that underlie the inappropriate synthesis of IL-17 and IL-21 in autoimmune diseases can thus provide important insights into potential therapies for these disorders. Here we have shown that the serine-threonine kinase Rho-associated, coiled-coil–containing protein kinase 2 (ROCK2) becomes activated in mouse T cells under Th17 skewing conditions and phosphorylates interferon regulatory factor 4 (IRF4), a transcription factor that is absolutely required for the production of IL-17 and IL-21. We furthermore demonstrated that ROCK2-mediated phosphorylation of IRF4 regulated the synthesis of IL-17 and IL-21 and the differentiation of Th17 cells. Whereas CD4+ T cells from WT mice activated ROCK2 physiologically under Th17 conditions, CD4+ T cells from 2 different mouse models of spontaneous autoimmunity aberrantly activated ROCK2 under neutral conditions. Moreover, administration of ROCK inhibitors ameliorated the deregulated production of IL-17 and IL-21 and the inflammatory and autoantibody responses observed in these autoimmune mice. Our findings thus uncover a crucial link among ROCK2, IRF4, and the production of IL-17 and IL-21 and support the idea that selective inhibition of ROCK2 could represent an important therapeutic regimen for the treatment of autoimmune disorders.

Authors

Partha S. Biswas, Sanjay Gupta, Emily Chang, Li Song, Roslynn A. Stirzaker, James K. Liao, Govind Bhagat, Alessandra B. Pernis

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Critical reviews in immunology 2012
Murine Models of Systemic Lupus Erythematosus
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Abnormalities of T cell signaling in systemic lupus erythematosus
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EMBO reports 2011
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S Bruhn, F Barrenäs, R Mobini, BA Andersson, S Chavali, BS Egan, E Hovig, GK Sandve, MA Langston, G Rogers, H Wang, M Benson
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Signal transduction pathways and transcriptional regulation in Th17 cell differentiation
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Cytokine & Growth Factor Reviews 2010
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Cellular Immunology 2010

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