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Involvement of 15‐lipoxygenase in the inflammatory arthritis
Author(s) -
Wu MingYueh,
Lin TzuHung,
Chiu YungCheng,
Liou HoungChi,
Yang RongSen,
Fu WenMei
Publication year - 2012
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.24098
Subject(s) - arthritis , rheumatoid arthritis , proinflammatory cytokine , inflammation , matrix metalloproteinase , synovial membrane , pi3k/akt/mtor pathway , medicine , protein kinase b , chemistry , inflammatory arthritis , arachidonate 5 lipoxygenase , pharmacology , cancer research , eicosanoid , immunology , phosphorylation , signal transduction , arachidonic acid , biochemistry , enzyme
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. J. Cell. Biochem. 113: 2279–2289, 2012. © 2012 Wiley Periodicals, Inc.