CDK inhibitors suppress Th17 and promote iTreg differentiation, and ameliorate experimental autoimmune encephalomyelitis in mice

• Published in: Biochemical and biophysical research communications Vol. 435; no. 3; pp. 378 - 384
• Main Authors: Yoshida, Hideyuki, Kotani, Hitoshi, Kondo, Taisuke, Tani, Ito, Wei, Xuetao, Tsuruta, Sanae, Kimura, Akihiro, Asakawa, Mayako, Ito, Minako, Nagai, Shigenori, Yoshimura, Akihiko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.06.2013
• Subjects: Animals; Benzazepines - pharmacology; CDK; Cell Differentiation - drug effects; Cell Differentiation - immunology; Cyclin-Dependent Kinases - antagonists & inhibitors; Cytokine signaling; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Helper T cells; Indoles - pharmacology; Mice; Mice, Inbred C57BL; Protein Kinase Inhibitors - pharmacology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology; Th17; Th17 Cells - drug effects; Th17 Cells - immunology; Th17 Cells - metabolism; CDK; Cytokine signaling; Th17; Helper T cells
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2013.04.096

•We screened 285 chemical inhibitors for known signaling pathways.•Two CDK inhibitors, Kenpaullone and Roscovitine suppressed Th17 differentiation.•CDK inhibitors suppressed experimental autoimmune encephalomyelitis (EAE).•CDK inhibitors enhanced STAT5 activation and modify the Th17/iTreg balance. 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.