TY - JOUR
T1 - CDK inhibitors suppress Th17 and promote iTreg differentiation, and ameliorate experimental autoimmune encephalomyelitis in mice
AU - Yoshida, Hideyuki
AU - Kotani, Hitoshi
AU - Kondo, Taisuke
AU - Tani, Ito
AU - Wei, Xuetao
AU - Tsuruta, Sanae
AU - Kimura, Akihiro
AU - Asakawa, Mayako
AU - Ito, Minako
AU - Nagai, Shigenori
AU - Yoshimura, Akihiko
N1 - Funding Information:
We thank the Screening Committee of Anticancer Drugs supported by a Grant-in-Aid for Scientific Research in the Priority Area “Cancer” from the Ministry of Education, Culture, Sports, Science and Technology, Tokyo, for providing us with SCADS inhibitor kits. This work was supported by special grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Intramural Research Grant (22-4) for Neurological and Psychiatric Disorders of NCNP, the SENSHIN Research Foundation , the Kanae Foundation for the Promotion of Medical Science, the Mochida Memorial Foundation , the Uehara Memorial Foundation and the Takeda Science Foundation .
PY - 2013/6/7
Y1 - 2013/6/7
N2 - 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.
AB - 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.
KW - CDK
KW - Cytokine signaling
KW - Helper T cells
KW - Th17
UR - http://www.scopus.com/inward/record.url?scp=84878974454&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84878974454&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2013.04.096
DO - 10.1016/j.bbrc.2013.04.096
M3 - Article
C2 - 23665028
AN - SCOPUS:84878974454
SN - 0006-291X
VL - 435
SP - 378
EP - 384
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -