Published online before print July 22, 2004, doi: 10.1161/01.ATV.0000140063.06341.09
© 2004 American Heart Association, Inc.
Vascular Biology |
Leukotriene B4 Strongly Increases Monocyte Chemoattractant Protein-1 in Human Monocytes
From the Departments of Cardiovascular Diseases (L.H., A.Z., S.D.W., M.S.S., J.E., J.C.), Drug Discovery Sciences (F.W., F.U.), and Infectious Diseases and Immunology (J.M.A., M.S.), Merck Research Laboratories, Rahway, NJ.
Correspondence to Jisong Cui, Department of Cardiovascular Diseases, Merck Research Laboratories, 126 E. Lincoln Avenue, P.O. Box 2000, RY80W-107, Rahway, NJ 07065. E-mail jisong_cui{at}merck.com
Objective— Leukotriene B4 (LTB4), a product of the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism, has been implicated in atherosclerosis. However, the molecular mechanisms for the atherogenic effect of LTB4 are not well understood. This study is to determine candidate mechanisms.
Method and Results—Primary human monocytes were treated with LTB4 and the supernatant was analyzed for cytokine/chemokine production by an immuno-protein array. This analysis revealed a strong increase of the monocyte chemoattractant protein-1 (MCP-1), a proinflammatory cytokine. Follow-up analyses with MCP-1 enzyme-linked immunosorbent assay (for quantitation of MCP-1 protein) and real-time polymerase chain reaction (PCR) (for MCP-1 mRNA) demonstrated that LTB4 strongly induced expression of MCP-1 protein and mRNA in a time-dependent and dose-dependent fashion. This induction was effectively abolished by CP-105,696, an antagonist for the LTB4 receptor BLT1. Selective inhibitors of ERK1/2 or JNK MAPK effectively blocked the LTB4-induced MCP-1 production. Furthermore, LTB4 increased NF-
B DNA binding activity, which was blocked by CP-105,696.
Conclusions— LTB4 strongly induces MCP-1 production in primary human monocytes. This induction is mediated through the BLT1 pathway increasing MCP-1 transcription. Activation of ERK1/2 or JNK MAPK is essential for this induction. The NF-B activation may be involved in LTB4-increased MCP-1 expression. The LTB4-induced MCP-1 in human monocytes may play a critical role in the atherogenicity of LTB4.
Leukotriene B4 (LTB4), a product of the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism, has been implicated in atherosclerosis. However, the molecular mechanisms for the atherogenic effect of LTB4 are not well understood. This study shows that the LTB4-induced MCP-1 in human monocytes may play a critical role in the atherogenicity of LTB4.
Key Words: leukotriene B4 • monocyte chemoattractant protein-1 • atherosclerosis • human monocytes
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