| First Author | Yoshida H | Year | 2013 |
| Journal | Biochem Biophys Res Commun | Volume | 435 |
| Issue | 3 | Pages | 378-84 |
| PubMed ID | 23665028 | Mgi Jnum | J:202641 |
| Mgi Id | MGI:5520145 | Doi | 10.1016/j.bbrc.2013.04.096 |
| Citation | Yoshida H, et al. (2013) CDK inhibitors suppress Th17 and promote iTreg differentiation, and ameliorate experimental autoimmune encephalomyelitis in mice. Biochem Biophys Res Commun 435(3):378-84 |
| abstractText | 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 RORgammat, 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 RORgammat 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. |
