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

Hideyuki Yoshida, Hitoshi Kotani, Taisuke Kondo, Ito Tani, Xuetao Wei, Sanae Tsuruta, Akihiro Kimura, Mayako Asakawa, Minako Ito, Shigenori Nagai, Akihiko Yoshimura

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)378-384
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume435
Issue number3
DOIs
Publication statusPublished - 2013 Jun 7

Fingerprint

kenpaullone
Autoimmune Experimental Encephalomyelitis
Autoimmune Diseases
Interleukin-2
Th17 Cells
Phosphorylation
T-cells
MAP Kinase Signaling System
Interleukin-6
T-Lymphocytes
roscovitine

Keywords

  • CDK
  • Cytokine signaling
  • Helper T cells
  • Th17

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

CDK inhibitors suppress Th17 and promote iTreg differentiation, and ameliorate experimental autoimmune encephalomyelitis in mice. / Yoshida, Hideyuki; Kotani, Hitoshi; Kondo, Taisuke; Tani, Ito; Wei, Xuetao; Tsuruta, Sanae; Kimura, Akihiro; Asakawa, Mayako; Ito, Minako; Nagai, Shigenori; Yoshimura, Akihiko.

In: Biochemical and Biophysical Research Communications, Vol. 435, No. 3, 07.06.2013, p. 378-384.

Research output: Contribution to journalArticle

Yoshida, Hideyuki ; Kotani, Hitoshi ; Kondo, Taisuke ; Tani, Ito ; Wei, Xuetao ; Tsuruta, Sanae ; Kimura, Akihiro ; Asakawa, Mayako ; Ito, Minako ; Nagai, Shigenori ; Yoshimura, Akihiko. / CDK inhibitors suppress Th17 and promote iTreg differentiation, and ameliorate experimental autoimmune encephalomyelitis in mice. In: Biochemical and Biophysical Research Communications. 2013 ; Vol. 435, No. 3. pp. 378-384.
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