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

PS Biswas, S Gupta, E Chang, L Song… - The Journal of …, 2010 - Am Soc Clin Investig
PS Biswas, S Gupta, E Chang, L Song, RA Stirzaker, JK Liao, G Bhagat, AB Pernis
The Journal of clinical investigation, 2010Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation