title: Selective inhibition of CDK7 ameliorates experimental arthritis in mice.
abstract: Cyclin-dependent kinases (CDKs) have emerged as anti-inflammatory targets. The purpose of this study was to explore the therapeutic effects of a selective CDK7 inhibitor, BS-181, on mice with established collagen-induced arthritis (CIA). CIA mice were administered intraperitoneally with BS-181 (10 mg/kg) twice daily for 2 weeks. Control mice received vehicle only. Arthritis severity and joint histopathology were examined. The proinflammatory cytokines and anti-type II collagen antibodies (anti-CII) were determined by ELISA. IkB kinase (IKK)-β/NF-κB activation in the arthritic joints was assessed by Western blot. The ratio of Th17 cells was determined by flow cytometry. In vitro, splenocytes from mice with established CIA were stimulated with CII in the presence or absence of BS-181 and cytokines were detected. BS-181 treatment reduced the clinical score and histological damage in CIA mice. The serum proinflammatory cytokines (IL-6, IL-1β and IL-17) and anti-CII IgG2a levels were also decreased by BS-181 administration. Moreover, IKK-β/NF-κB signaling pathway was inhibited in arthritic joints. BS-181 administration also decreased the ratio of Th17 cells. In addition, CIA splenocytes pretreated with BS-181 produced less proinflammatory cytokines in vitro. These findings indicate that CDK7 inhibition by BS-181 is effective in the treatment of CIA, which might be mediated by suppression of IKK-β/NF-κB activation and Th17 cell response.
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, No. 74 Zhongshan 2nd Road, Guangzhou, 510080, People's Republic of China, gysyxy@gmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Lin
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Liu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Hong-Hai
authors.initials: HH
authors.lastname: Hong
authors.forename: Xu-Guang
authors.initials: XG
authors.lastname: Guo
authors.forename: Guo-Quan
authors.initials: GQ
authors.lastname: Gao
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001169:Arthritis, Experimental / Q000473:pathology* / Q000628:therapy*; D001323:Autoantibodies / Q000097:blood; D015153:Blotting, Western; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051550:I-kappa B Kinase / Q000032:analysis; D008297:Male; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000032:analysis; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D012720:Severity of Illness Index; D058504:Th17 Cells / Q000276:immunology; D016896:Treatment Outcome; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D000893:Anti-Inflammatory Agents; D001323:Autoantibodies; D018844:Cyclin-Dependent Kinases; D016207:Cytokines; D051550:I-kappa B Kinase; D016328:NF-kappa B; D011720:Pyrazoles; D011743:Pyrimidines; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000592924:BS-181; C090586:Cdk7 protein, mouse