title: CDK inhibitors suppress Th17 and promote iTreg differentiation, and ameliorate experimental autoimmune encephalomyelitis in mice.
abstract: Th17 cells, which have been implicated in autoimmune diseases, require IL-6 and TGF-β for early differentiation. Several Smad-independent pathways including the JNK and the RhoA-ROCK pathways have been implicated in the induction of RORγt, 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-β and CDK inhibitor, efficiently suppressed TGF-β-mediated RORγt induction and enhanced Foxp3 induction in primary T cells. Another CDK inhibitor, Roscovitine, but not other GSK3-β 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-β. These data suggest that CDK inhibitors modulate TGF-β-signaling pathways, which restore TGF-β-mediated suppression of IL-2 production, thereby modifying the Th17/iTreg balance.
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshida
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kotani
authors.forename: Taisuke
authors.initials: T
authors.lastname: Kondo
authors.forename: Ito
authors.initials: I
authors.lastname: Tani
authors.forename: Xuetao
authors.initials: X
authors.lastname: Wei
authors.forename: Sanae
authors.initials: S
authors.lastname: Tsuruta
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kimura
authors.forename: Mayako
authors.initials: M
authors.lastname: Asakawa
authors.forename: Minako
authors.initials: M
authors.lastname: Ito
authors.forename: Shigenori
authors.initials: S
authors.lastname: Nagai
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D001552:Benzazepines; D007211:Indoles; D047428:Protein Kinase Inhibitors; C119620:kenpaullone; D018844:Cyclin-Dependent Kinases