Published online before print February 13, 2003, doi: 10.1161/01.ATV.0000060891.31516.24
© 2003 American Heart Association, Inc.
Vascular Biology |
Oncostatin M, an Interleukin-6 Family Cytokine, Upregulates Matrix Metalloproteinase-9 Through the Mitogen-Activated Protein Kinase Kinase-Extracellular Signal-Regulated Kinase Pathway in Cultured Smooth Muscle Cells
From the Cardiovascular Research Institute and Internal Medicine III (T.N., H.K., R.S., M.K. T.I), Kurume University School of Medicine, Kurume; and Department of Immunology (A.Y.), Research Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Correspondence to Hisashi Kai, MD, PhD, Cardiovascular Research Institute and Internal Medicine III, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. E-mail naikai{at}med.kurume-u.ac.jp
Objectives— Matrix metalloproteinase (MMP)-9 is implicated in extracellular matrix (ECM) degradation of atherosclerotic lesions. Oncostatin M (OSM) regulates ECM metabolism in various kinds of cells. Thus, we sought to investigate whether OSM regulates MMP-9 expression in cultured rat aortic smooth muscle cells (SMCs) and, if so, to determine the signaling pathway for MMP-9 induction by OSM.
Methods and Results— Competitive reverse transcriptase polymerase chain reaction showed that OSM upregulated MMP-9 mRNA expression, peaking at 4 hours and returning to unstimulated levels by 24 hours. Gelatin zymography revealed that MMP-9 activity was increased in the conditioned medium after the 24-hour OSM treatment. Immunoblot analysis demonstrated that OSM transiently induced extracellular signal-regulated kinase (ERK)1/2 and STAT3 phosphorylations with a peak at 15 and 5 minutes, respectively. A MEK1 inhibitor, PD98059, not only blocked ERK1/2 phosphorylation but also abolished the OSM-induced MMP-9 upregulation, whereas the MMP-9 induction was not affected by overexpressing dominant-negative STAT3. In addition, OSM slightly upregulated MMP-2 and downregulated tissue inhibitors of MMP-1 and -3 through different mechanisms from that in case of MMP-9.
Conclusions— OSM upregulates MMP-9 expression in SMCs through the MEK-ERK but not STAT3 pathway.
Key Words: oncostatin M • matrix metalloproteinase • muscle • smooth • signal transduction
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