Effect of nuclear factor-kappaB inhibition on rheumatoid fibroblast-like synoviocytes and collagen induced arthritis.
OBJECTIVE
The nuclear factor-kB (NF-kB) signaling pathway has been implicated as a molecular target for the treatment of various inflammatory diseases, such as rheumatoid arthritis (RA). In particular, IkB kinase (IKK) is considered an important molecular target because the majority of inflammatory signaling pathways mediated by NF-kB involve IKK activation. We investigated the effect of NF-kB inhibition on rheumatoid fibroblast-like synoviocytes (FLS) and collagen induced arthritis.


METHODS
We evaluated the effect of IMD-0560, an inhibitor of IKK, on rheumatoid FLS in vitro and on collagen type II induced arthritis in mice.


RESULTS
IMD-0560 suppressed the nuclear translocation of NF-kB and phosphorylation of IkBa induced by tumor necrosis factor-a in FLS. In addition, this compound suppressed the production of inflammatory cytokines, including interleukin 6 (IL-6), IL-8, and monocyte chemoattractant protein-1. IMD-0560 also inhibited the proliferation of FLS without showing cellular toxicity. Finally, this compound was effective against collagen induced arthritis in mice.


CONCLUSIONS
Based on these results, IMD-0560 could be a new therapeutic agent for RA.
Okazaki
Yuko
Y
Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Japan. okazaki@tkf.att.ne.jp
Sawada
Tetsuji
T
Nagatani
Katsuya
K
Komagata
Yoshinori
Y
Inoue
Tetsufumi
T
Muto
Susumu
S
Itai
Akiko
A
Yamamoto
Kazuhiko
K
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D001549:Benzamides / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects*
D001549:Benzamides; D016207:Cytokines; D020672:I-kappa B Proteins; C503742:N-(2,5-bis(trifluoromethyl)phenyl)-5-bromo-2-hydroxybenzamide; D016328:NF-kappa B