Journal
BIOCHEMICAL PHARMACOLOGY
Volume 76, Issue 1, Pages 79-90Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2008.04.006
Keywords
inflammatory genes; rheumatoid arthritis; NF-kappa B; cytokines : chemokines
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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 E2, and the chemokines, RANTES, GRO alpha, and ENA-78, in cytokine-stimulated human synoviocytes. CT20126 suppressed NF-kappa B activation and iNOS promoter activity, which correlated with its inhibitory effect on phosphorylation-dependent I kappa B kinase activation, I kappa B phosphorylation and degradation, and NF-kappa B nuclear translocation, in LPS-stimulated macrophages. This compound also inhibited LPS-induced NF-kappa B-inducing kinase (NIK) and Akt phosphorylation, which are upstream of NF-kappa B 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-kappa B-responsive inflammatory gene expression by inhibiting the NIK- and Akt-dependent canonical NF-kappa B pathway and can be used as a therapeutic agent for rheumatoid arthritis related to chronic inflammation. (c) 2008 Elsevier Inc. All rights reserved.
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