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.
Copyright © 2012 Wiley Periodicals, Inc.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Arachidonate 15-Lipoxygenase / genetics
-
Arachidonate 15-Lipoxygenase / metabolism*
-
Arthritis, Experimental / metabolism
-
Arthritis, Experimental / pathology
-
Arthritis, Rheumatoid / enzymology*
-
Arthritis, Rheumatoid / pathology
-
Cells, Cultured
-
Chromones / pharmacology
-
Eicosapentaenoic Acid / analogs & derivatives
-
Eicosapentaenoic Acid / genetics
-
Fibroblasts / metabolism
-
Fibroblasts / pathology
-
Fluorenes / pharmacology
-
Humans
-
I-kappa B Kinase / metabolism
-
Interleukin-1beta / metabolism
-
Matrix Metalloproteinase 2 / genetics*
-
Matrix Metalloproteinase 2 / metabolism
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Morpholines / pharmacology
-
Phosphatidylinositol 3-Kinases / metabolism
-
Phosphoinositide-3 Kinase Inhibitors
-
Phosphorylation
-
Proline / analogs & derivatives
-
Proline / pharmacology
-
Proto-Oncogene Proteins c-akt / metabolism
-
RNA Interference
-
RNA, Messenger / genetics
-
RNA, Small Interfering
-
Synovial Membrane / metabolism
-
Synovial Membrane / pathology
-
Thiocarbamates / pharmacology
-
Transcription Factor RelA / antagonists & inhibitors
-
Transcription Factor RelA / metabolism
-
Tumor Necrosis Factor-alpha / metabolism
Substances
-
6,11-dihydro-5-thia-11-aza-benzo(a)-fluorene
-
Chromones
-
Fluorenes
-
Interleukin-1beta
-
Morpholines
-
Phosphoinositide-3 Kinase Inhibitors
-
RNA, Messenger
-
RNA, Small Interfering
-
Thiocarbamates
-
Transcription Factor RelA
-
Tumor Necrosis Factor-alpha
-
prolinedithiocarbamate
-
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
-
15-hydroxy-5,8,11,13,17-eicosapentaenoic acid
-
Proline
-
Eicosapentaenoic Acid
-
Arachidonate 15-Lipoxygenase
-
Proto-Oncogene Proteins c-akt
-
I-kappa B Kinase
-
Matrix Metalloproteinase 2