title: Cysteinyl leukotrienes induce monocyte chemoattractant protein-1 in human monocyte/macrophages via mitogen-activated protein kinase and nuclear factor-kappaB pathways.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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-kappaB (NF-kappaB) 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-kappaB and pranlukast as a CysLT1 receptor antagonist on induction of MCP-1 production by LTD(4) and LTC(4).
  
  
  RESULTS
  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-kappaB activation was induced by addition of LTD(4) and LTC(4). Pretreatment with the NF-kappaB inhibitors caffeic acid phenylethyl ester and MG-132 inhibited MCP-1 production by CysLTs. Pranlukast inhibited phosphorylation of ERK1/2 and JNK, NF-kappaB activation, and the MCP-1 production induced by CysLTs.
  
  
  CONCLUSIONS
  CysLTs induce MCP-1 and this induction is mediated by ERK1/2 and JNK in MAPK, and NF-kappaB pathways via the CysLT1 receptor, for the most part, in human monocytes/macrophages.
authors.affiliation: Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Ichiyama
authors.forename: Masanari
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Shunji
authors.initials: S
authors.lastname: Hasegawa
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Matsubara
authors.forename: Susumu
authors.initials: S
authors.lastname: Furukawa
mesh_terms: D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D006801:Humans; D017997:Leukotriene C4 / Q000276:immunology* / Q000494:pharmacology; D017998:Leukotriene D4 / Q000276:immunology* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000819:agonists / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018077:Receptors, Leukotriene / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D018932:Chemokine CCL2; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D018077:Receptors, Leukotriene; D017997:Leukotriene C4; D017998:Leukotriene D4; D020928:Mitogen-Activated Protein Kinases; C083169:leukotriene D4 receptor