Cysteinyl Leukotrienes Induce Monocyte Chemoattractant Protein-1 in Human Monocyte/Macrophages via Mitogen-Activated Protein Kinase and Nuclear Factor-κB 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-κB (NF-κB) by leukotriene (LT) D₄ and LTC₄ 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 LTD₄ and LTC₄. Results: LTD₄ and LTC₄ 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 LTD₄ and LTC₄. 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. Conclusion: 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.

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

“…Monocytes/macrophages isolated from peripheral blood MNCs express CysLT 1 R mRNA either in large excess compared with CysLT 2 R transcript levels (Lötzer et al, 2003) or, exclusively, such as in U937 , a human leukemic monocyte/macrophage cell line. This correlates with the finding that cysteinyl LTs contribute to inflammatory reactions by induction of MCP-1 via the CCR2B receptor in THP-1 cells Woszczek et al, 2005;Hashimoto et al, 2009). This reported induction by MCP-1 was also observed in another monocytic leukemia cell line and was further supported by the enhanced activation of chemotactic activity observed in human monocytes (Woszczek et al, 2008a).…”

Hippocampal CysLT1R knockdown or blockade represses LPS-induced depressive behaviors and neuroinflammatory response in mice

“…Hippocampal CysLT 1 R expression was up-regulated by LPS exposure in mice and reversed by FLX Inflammation challenge by LPS administration has long been applied to induce depressive-like and anxiety-like behaviors in animal models [23,24] . Accordingly, we explored whether LPS exposure changed CysLT 1 R expression in the mouse hippocampus using a Western blot assay.…”

“…Hippocampal CysLT 1 R knockdown or blockade inhibited LPSinduced activation of the NF-κB pathway and production of proinflammatory cytokines CysLT 1 R has been reported to be implicated in neuroinflammation by regulating the NF-κB signaling pathway [23][24][25][26] , and LPS exposure activates NF-κB signaling by inducing the nuclear translocation of p65 [27] . To explore whether CysLT 1 R is involved in LPS-activated NF-κB signaling, the hippocampal level of NF-κB p65 in the nuclear fraction was detected by Western blot analysis.…”

Leukotriene C4 prevents the complete maturation of murine dendritic cells and modifies interleukin-12/interleukin-23 balance

“…54 Binding of CysLT with their receptors triggers the phosphorylation of MAPK. 18,19 Hashimoto et al 55 demonstrated that IL-10 production in human DCs stimulated with Zy was dependent on ERK and p38 MAPK activation. Also, the phagocytosis of opsonized particles by macrophages cultured with LTD 4 or LTC 4 was associated with p38 activation.…”