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

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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 E2 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, GROα, and ENA-78, in cytokine-stimulated human synoviocytes. CT20126 suppressed NF-κB activation and iNOS promoter activity, which correlated with its inhibitory effect on phosphorylation-dependent IκB kinase activation, IκB phosphorylation and degradation, and NF-κB nuclear translocation, in LPS-stimulated macrophages. This compound also inhibited LPS-induced NF-κB-inducing kinase (NIK) and Akt phosphorylation, which are upstream of NF-κB 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-κB-responsive inflammatory gene expression by inhibiting the NIK- and Akt-dependent canonical NF-κB pathway and can be used as a therapeutic agent for rheumatoid arthritis related to chronic inflammation.

Original languageEnglish
Pages (from-to)79-90
Number of pages12
JournalBiochemical Pharmacology
Volume76
Issue number1
DOIs
Publication statusPublished - 2008 Jul 1

Fingerprint

Experimental Arthritis
Gene Expression Regulation
Immunosuppressive Agents
Gene expression
Collagen
Down-Regulation
Chemical activation
Phosphorylation
Lipopolysaccharides
Nitric Oxide Synthase Type II
Phosphotransferases
Macrophages
Cyclooxygenase 2
Chemokines
Dinoprostone
Arthritis
Nitric Oxide
Anti-Inflammatory Agents
Cytokines
Chemokine CCL5

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Cite this

Lee, Seon Jin ; Nam, Woo Dong ; Na, Hee Jun ; Cho, Young Lai ; Ha, Kwon Soo ; Hwang, Jong Yun ; Lee, Hansoo ; Kim, Soon Ok ; Kwon, Young Guen ; Kim, Young Myeong. / CT20126, a novel immunosuppressant, prevents collagen-induced arthritis through the down-regulation of inflammatory gene expression by inhibiting NF-κB activation. In: Biochemical Pharmacology. 2008 ; Vol. 76, No. 1. pp. 79-90.
@article{9e0ca5baf74640b5a4d72496a67c2b28,
title = "CT20126, a novel immunosuppressant, prevents collagen-induced arthritis through the down-regulation of inflammatory gene expression by inhibiting NF-κB 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 E2 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, GROα, and ENA-78, in cytokine-stimulated human synoviocytes. CT20126 suppressed NF-κB activation and iNOS promoter activity, which correlated with its inhibitory effect on phosphorylation-dependent IκB kinase activation, IκB phosphorylation and degradation, and NF-κB nuclear translocation, in LPS-stimulated macrophages. This compound also inhibited LPS-induced NF-κB-inducing kinase (NIK) and Akt phosphorylation, which are upstream of NF-κB 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-κB-responsive inflammatory gene expression by inhibiting the NIK- and Akt-dependent canonical NF-κB pathway and can be used as a therapeutic agent for rheumatoid arthritis related to chronic inflammation.",
author = "Lee, {Seon Jin} and Nam, {Woo Dong} and Na, {Hee Jun} and Cho, {Young Lai} and Ha, {Kwon Soo} and Hwang, {Jong Yun} and Hansoo Lee and Kim, {Soon Ok} and Kwon, {Young Guen} and Kim, {Young Myeong}",
year = "2008",
month = "7",
day = "1",
doi = "10.1016/j.bcp.2008.04.006",
language = "English",
volume = "76",
pages = "79--90",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "1",

}

CT20126, a novel immunosuppressant, prevents collagen-induced arthritis through the down-regulation of inflammatory gene expression by inhibiting NF-κB activation. / Lee, Seon Jin; Nam, Woo Dong; Na, Hee Jun; Cho, Young Lai; Ha, Kwon Soo; Hwang, Jong Yun; Lee, Hansoo; Kim, Soon Ok; Kwon, Young Guen; Kim, Young Myeong.

In: Biochemical Pharmacology, Vol. 76, No. 1, 01.07.2008, p. 79-90.

Research output: Contribution to journalArticle

TY - JOUR

T1 - CT20126, a novel immunosuppressant, prevents collagen-induced arthritis through the down-regulation of inflammatory gene expression by inhibiting NF-κB activation

AU - Lee, Seon Jin

AU - Nam, Woo Dong

AU - Na, Hee Jun

AU - Cho, Young Lai

AU - Ha, Kwon Soo

AU - Hwang, Jong Yun

AU - Lee, Hansoo

AU - Kim, Soon Ok

AU - Kwon, Young Guen

AU - Kim, Young Myeong

PY - 2008/7/1

Y1 - 2008/7/1

N2 - 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 E2 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, GROα, and ENA-78, in cytokine-stimulated human synoviocytes. CT20126 suppressed NF-κB activation and iNOS promoter activity, which correlated with its inhibitory effect on phosphorylation-dependent IκB kinase activation, IκB phosphorylation and degradation, and NF-κB nuclear translocation, in LPS-stimulated macrophages. This compound also inhibited LPS-induced NF-κB-inducing kinase (NIK) and Akt phosphorylation, which are upstream of NF-κB 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-κB-responsive inflammatory gene expression by inhibiting the NIK- and Akt-dependent canonical NF-κB pathway and can be used as a therapeutic agent for rheumatoid arthritis related to chronic inflammation.

AB - 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 E2 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, GROα, and ENA-78, in cytokine-stimulated human synoviocytes. CT20126 suppressed NF-κB activation and iNOS promoter activity, which correlated with its inhibitory effect on phosphorylation-dependent IκB kinase activation, IκB phosphorylation and degradation, and NF-κB nuclear translocation, in LPS-stimulated macrophages. This compound also inhibited LPS-induced NF-κB-inducing kinase (NIK) and Akt phosphorylation, which are upstream of NF-κB 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-κB-responsive inflammatory gene expression by inhibiting the NIK- and Akt-dependent canonical NF-κB pathway and can be used as a therapeutic agent for rheumatoid arthritis related to chronic inflammation.

UR - http://www.scopus.com/inward/record.url?scp=45049088307&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=45049088307&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2008.04.006

DO - 10.1016/j.bcp.2008.04.006

M3 - Article

C2 - 18513703

AN - SCOPUS:45049088307

VL - 76

SP - 79

EP - 90

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 1

ER -