Pathophysiological role of mast cells in collagen-induced arthritis: study with a cysteinyl leukotriene receptor antagonist, montelukast.
Our previous study showed that the number of mast cells was increased in the inflamed paws of collagen-induced arthritis in mice, and treatment with a mast cell-stabilizing compound effectively suppressed the development of collagen-induced arthritis. A recent in vitro study showed that mast cells express cysteinyl leukotriene type 1 receptor, and that a cysteinyl leukotriene type 1 receptor antagonist inhibits the production of TNF-alpha by mast cells. To further investigate the role of mast cells in vivo, we evaluated the therapeutic effects of a cysteinyl leukotriene type 1 receptor antagonist, montelukast, on the development of collagen-induced arthritis in mice. Montelukast (10 mg/kg/day) or vehicle was orally administered to mice for 12 weeks, starting 6 weeks after immunization with bovine type II collagen. Treatment with montelukast significantly reduced clinical scores and X-ray scores of collagen-induced arthritis, and decreased the number of mast cells in the inflamed paws of collagen-induced arthritic mice. Immunohistochemical analysis revealed that mast cells in the inflamed synovium were one of the major cells producing TNF-alpha and that the number of TNF-alpha positive mast cells was significantly reduced by treatment with montelukast. Furthermore, TNF-alpha and SCF mRNA levels in the paws of collagen-induced arthritic mice were markedly decreased by montelukast treatment. Montelukast may lead to a beneficial therapeutic effect by inhibiting TNF-alpha production by mast cells.
Shiota
Naotaka
N
Department of Pharmacology, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan. shiotana@med.shimane-u.ac.jp
Shimoura
Keiko
K
Okunishi
Hideki
H
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003521:Cyclopropanes; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D008297:Male; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000085:Acetates; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D011804:Quinolines; D012333:RNA, Messenger; D019089:Stem Cell Factor; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha; C093875:montelukast