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
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
VL - 435
SP - 378
EP - 384
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 3
ER -