title: Involvement of 15-lipoxygenase in the inflammatory arthritis.
abstract: 15-Lipoxygenase (15-LOX) is involved in many pathological processes. The aim of this study is to examine the role of 15-LOX in the matrix metalloproteinase (MMP) expression and inflammatory arthritis. It was found that treatment of 15-LOX downstream product of 15-(S)-HETE (15-S-hydroxyeicosatetraenoic acid) increased the mRNA and protein levels of MMP-2 in rheumatoid arthritis synovial fibroblast (RASF) derived from rheumatoid arthritis patients. The enhancement effect of 15-(S)-HETE was antagonized by the addition of LY294002 (PI3K inhibitor) and PDTC (NF-κB inhibitor). Treatment of 15-(S)-HETE increased the phosphorylation of AKT, nuclear translocation of p65 and the breakdown of IκBα. TNF-α and IL-1β are the key cytokines involved in arthritis and also increase the activity of MMP-2 in RASF, which was antagonized by pretreatment with 15-LOX inhibitor PD146176 or knockdown of 15-LOX. It was also found that these two cytokines increased the expression of 15-LOX in RASF. Treatment of glucocorticoid but not NSAIDs inhibited 15-(S)-HETE-induced expression of MMP-2. In comparison with wild-type mice, adjuvant-induced arthritis and MMP-2 expression in synovial membrane were markedly inhibited in 15-LOX knockout (KO) mice. These results indicate that 15-LOX plays an important role in the disease progression of arthritis and may be involved in the inflammatory action induced by TNF-α and IL-1β. 15-LOX is thus a good target for developing drugs in the treatment of inflammatory arthritis.
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ming-Yueh
authors.initials: MY
authors.lastname: Wu
authors.forename: Tzu-Hung
authors.initials: TH
authors.lastname: Lin
authors.forename: Yung-Cheng
authors.initials: YC
authors.lastname: Chiu
authors.forename: Houng-Chi
authors.initials: HC
authors.lastname: Liou
authors.forename: Rong-Sen
authors.initials: RS
authors.lastname: Yang
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Fu
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000473:pathology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005449:Fluorenes / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D013859:Thiocarbamates / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001093:Arachidonate 15-Lipoxygenase; D002867:Chromones; D015118:Eicosapentaenoic Acid; D005449:Fluorenes; D051550:I-kappa B Kinase; D053583:Interleukin-1beta; D020778:Matrix Metalloproteinase 2; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011392:Proline; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013859:Thiocarbamates; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C106248:6,11-dihydro-5-thia-11-aza-benzo(a)-fluorene; C066229:prolinedithiocarbamate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C059164:15-hydroxy-5,8,11,13,17-eicosapentaenoic acid