화학공학소재연구정보센터
Biochemical and Biophysical Research Communications, Vol.435, No.3, 378-384, 2013
CDK inhibitors suppress Th17 and promote iTreg differentiation, and ameliorate experimental autoimmune encephalomyelitis in mice
Th17 cells, which have been implicated in autoimmune diseases, require IL-6 and TGF-beta for early differentiation. Several Smad-independent pathways including the JNK and the RhoA-ROCK pathways have been implicated in the induction of ROR gamma t, the master regulator of Th17, however, molecular mechanisms underlying Smad-independent pathway remain largely unknown. To identify novel pathways involved in Th17 differentiation, we screened 285 chemical inhibitors for known signaling pathways. Among them, we found that Kenpaullone, a GSK3-beta and CDK inhibitor, efficiently suppressed TGF-beta-mediated ROR gamma t induction and enhanced Foxp3 induction in primary T cells. Another CDK inhibitor, Roscovitine, but not other GSK3-beta inhibitors, suppressed Th17 differentiation and enhanced iTreg development. Kenpaullone and Roscovitine suppressed experimental autoimmune encephalomyelitis (EAE), a typical Th17-mediated autoimmune disease model. These two compounds enhanced STAT5 phosphorylation and restored IL-2 production in the presence of TGF-beta. These data suggest that CDK inhibitors modulate TGF-beta-signaling pathways, which restore TGF-beta-mediated suppression of IL-2 production, thereby modifying the Th17/iTreg balance. (C) 2013 Elsevier Inc. All rights reserved.