We have previously demonstrated that cysteinyl leukotriene (CysLT) induced monocyte chemoattractant protein-1 (MCP-1) production in monocytes/macrophages. The intracellular signal transduction pathway of MCP-1 production induced by CysLT in human monocytes/macrophages is unclear. The activation of mitogen-activated protein kinase (MAPK), including extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 MAPK by phosphorylation, and nuclear factor-κB (NF-κB) by leukotriene (LT) D 4 and LTC 4 was determined in THP-1 cells, a human monocytic leukemia cell line, and peripheral blood CD14+ monocytes/macrophages. We examined the inhibitory effects of inhibitors of ERK1/2, JNK, p38 MAPK and NF-κB and pranlukast as a CysLT1 receptor antagonist on induction of MCP-1 production by LTD 4 and LTC 4. LTD 4 and LTC 4 induced significant phosphorylations of ERK1/2 and JNK, but not p38 MAPK, in THP-1 cells and peripheral blood CD14+ monocytes/macrophages. Pretreatment with the ERK1/2 inhibitor PD98059 and JNK inhibitor SP600125 attenuated MCP-1 production by CysLTs. NF-κB activation was induced by addition of LTD 4 and LTC 4. Pretreatment with the NF-κB inhibitors caffeic acid phenylethyl ester and MG-132 inhibited MCP-1 production by CysLTs. Pranlukast inhibited phosphorylation of ERK1/2 and JNK, NF-κB activation, and the MCP-1 production induced by CysLTs. CysLTs induce MCP-1 and this induction is mediated by ERK1/2 and JNK in MAPK, and NF-κB pathways via the CysLT1 receptor, for the most part, in human monocytes/macrophages.