CT20126, a novel immunosuppressant, prevents collagen-induced arthritis through the down-regulation of inflammatory gene expression by inhibiting NF-kappaB activation.
The colchicine-derived CT20126 compound has recently been shown to exert an immune regulatory effect and prolong the survival of allograft skins. In this study, we explored the anti-inflammatory and anti-arthritic effects of CT20126 in vivo and in vitro as well as investigated its underlying action mechanism. CT20126 suppressed the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2, tumor necrosis factor-alpha, and interleukin-1beta as well as the production of nitric oxide and prostaglandin E(2) in lipopolysaccharide (LPS)-treated macrophages as well as LPS-administered mice. This drug also inhibited the production of nitric oxide, prostaglandin E(2), and the chemokines, RANTES, GROalpha, and ENA-78, in cytokine-stimulated human synoviocytes. CT20126 suppressed NF-kappaB activation and iNOS promoter activity, which correlated with its inhibitory effect on phosphorylation-dependent IkappaB kinase activation, IkappaB phosphorylation and degradation, and NF-kappaB nuclear translocation, in LPS-stimulated macrophages. This compound also inhibited LPS-induced NF-kappaB-inducing kinase (NIK) and Akt phosphorylation, which are upstream of NF-kappaB activation. Furthermore, CT20126 significantly decreased the incidence and severity of arthritis as well as inhibited the expression of inflammatory cytokines, chemokines, iNOS, and cyclooxygenase-2 in the paws of collagen-induced arthritic mice. These findings indicate that CT20126 exerts an anti-inflammatory effect through NF-kappaB-responsive inflammatory gene expression by inhibiting the NIK- and Akt-dependent canonical NF-kappaB pathway and can be used as a therapeutic agent for rheumatoid arthritis related to chronic inflammation.
Lee
Seon-Jin
SJ
Department of Molecular and Cellular Biochemistry and Vascular System Research Center, School of Medicine, Kangwon National University, Chunchon, Kangwon-Do 200-701, Republic of Korea.
Nam
Woo-Dong
WD
Na
Hee-Jun
HJ
Cho
Young-Lai
YL
Ha
Kwon-Soo
KS
Hwang
Jong-Yun
JY
Lee
Hansoo
H
Kim
Soon-Ok
SO
Kwon
Young-Guen
YG
Kim
Young-Myeong
YM
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000517:prevention & control*; D003078:Colchicine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003094:Collagen / Q000009:adverse effects*; D015536:Down-Regulation / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
C520374:CT20126; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D016328:NF-kappa B; D003094:Collagen; D003078:Colchicine