Leukotriene B4Strongly Increases Monocyte Chemoattractant Protein-1 in Human Monocytes

Abstract

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 LTB₄are not well understood. This study is to determine candidate mechanisms.Method and Results—Primary human monocytes were treated with LTB₄and 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 LTB₄strongly 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 LTB₄receptor BLT₁. Selective inhibitors of ERK1/2 or JNK MAPK effectively blocked the LTB₄-induced MCP-1 production. Furthermore, LTB₄increased NF-κB DNA binding activity, which was blocked by CP-105,696.Conclusions—LTB₄strongly induces MCP-1 production in primary human monocytes. This induction is mediated through the BLT₁pathway increasing MCP-1 transcription. Activation of ERK1/2 or JNK MAPK is essential for this induction. The NF-κB 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.