Effect of a small molecule inhibitor of nuclear factor-kappaB nuclear translocation in a murine model of arthritis and cultured human synovial cells.
A small cell-permeable compound, dehydroxymethylepoxyquinomicin (DHMEQ), does not inhibit phosphorylation and degradation of IkappaB (inhibitor of nuclear factor-kappaB [NF-kappaB]) but selectively inhibits nuclear translocation of activated NF-kappaB. This study aimed to demonstrate the antiarthritic effect of this novel inhibitor of the NF-kappaB pathway in vivo in a murine arthritis model and in vitro in human synovial cells. Collagen-induced arthritis was induced in mice, and after onset of arthritis the mice were treated with DHMEQ (5 mg/kg body weight per day). Using fibroblast-like synoviocyte (FLS) cell lines established from patients with rheumatoid arthritis (RA), NF-kappaB activity was examined by electrophoretic mobility shift assays. The expression of molecules involved in RA pathogenesis was determined by RT-PCR, ELISA, and flow cytometry. The proliferative activity of the cells was estimated with tritiated thymidine incorporation. After 14 days of treatment with DHMEQ, mice with collagen-induced arthritis exhibited decreased severity of arthritis, based on the degree of paw swelling, the number of swollen joints, and radiographic and histopathologic scores, compared with the control mice treated with vehicle alone. In RA FLS stimulated with tumor necrosis factor-alpha, activities of NF-kappaB components p65 and p50 were inhibited by DHMEQ, leading to suppressed expression of the key inflammatory cytokine IL-6, CC chemokine ligand-2 and -5, matrix metalloproteinase-3, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. The proliferative activity of the cells was also suppressed. This is the first demonstration of an inhibitor of NF-kappaB nuclear translocation exhibiting a therapeutic effect on established murine arthritis, and suppression of inflammatory mediators in FLS was thought to be among the mechanisms underlying such an effect.
Wakamatsu
Kyoko
K
Department of Microbiology and Immunology, Tokyo Medical and Dental University Graduate School of Health Sciences, Tokyo, Japan. kyoko.wakamatsu@mac.com
Nanki
Toshihiro
T
Miyasaka
Nobuyuki
N
Umezawa
Kazuo
K
Kubota
Tetsuo
T
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003512:Cyclohexanones / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006614:Hindlimb; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014178:Translocation, Genetic
D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; D012333:RNA, Messenger; C464444:dehydroxymethylepoxyquinomicin