CT20126, a novel immunosuppressant, prevents collagen-induced arthritis through the down-regulation of inflammatory gene expression by inhibiting NF-kappaB activation.

Abstract

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.

• Authors: Seon-Jin Lee, Woo-Dong Nam, Hee-Jun Na, Young-Lai Cho, Kwon-Soo Ha, Jong-Yun Hwang, Hansoo Lee, Soon-Ok Kim, Young-Guen Kwon, Young-Myeong Kim
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 76 Issue 1 Pg. 79-90 (Jul 01 2008) ISSN: 1873-2968 [Electronic] England
• PMID: 18513703 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CT20126
• Immunosuppressive Agents
• Inflammation Mediators
• NF-kappa B
• Collagen
• Colchicine

Topics

• Animals
• Arthritis, Experimental (genetics, prevention & control)
• Colchicine (analogs & derivatives, pharmacology)
• Collagen (adverse effects)
• Down-Regulation (drug effects)
• Gene Expression Regulation (drug effects)
• Humans
• Immunohistochemistry
• Immunosuppressive Agents (pharmacology)
• Inflammation Mediators (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred DBA
• NF-kappa B (antagonists & inhibitors)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)