Metabolic products of soluble epoxide hydrolase are essential for monocyte chemotaxis to MCP-1 in vitro and in vivo

Suman Kundu, Talat Roome, Ashish Bhattacharjee, Kevin A. Carnevale, Valentin P. Yakubenko, Renliang Zhang, Sung Hee Hwang, Bruce D. Hammock, Martha K. Cathcart

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Monocyte chemoattractant protein-1 (MCP-1)-induced monocyte chemotaxis is a major event in inflammatory disease. Our prior studies have demonstrated that MCP-1-dependent chemotaxis requires release of arachidonic acid (AA) by activated cytosolic phospholipase A2 (cPLA2). Here we investigated the involvement of AA metabolites in chemotaxis. Neither cyclooxygenase nor lipoxygenase pathways were required, whereas pharmacologic inhibitors of both the cytochrome-P450 (CYP) and the soluble epoxide hydrolase (sEH) pathways blocked monocyte chemotaxis to MCP-1. To verify specificity, we demonstrated that the CYP and sEH products epoxyeiscosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs), respectively, restored chemotaxis in the presence of the inhibitors, indicating that sEH-derived products are essential for MCP-1-driven chemotaxis. Importantly, DHETs also rescued chemotaxis in cPLA2-deficient monocytes and monocytes with blocked Erk1/2 activity, because Erk controls cPLA2 activation. The in vitro findings regarding the involvement of CYP/sEH pathways were further validated in vivo using two complementary approaches measuring MCP-1-dependent chemotaxis in mice. These observations reveal the importance of sEH in MCP-1-regulated monocyte chemotaxis and may explain the observed therapeutic value of sEH inhibitors in treatment of inflammatory diseases, cardiovascular diseases, pain, and even carcinogenesis. Their effectiveness, often attributed to increasing EET levels, is probably influenced by the impairment of DHET formation and inhibition of chemotaxis.

Original languageEnglish (US)
Pages (from-to)436-447
Number of pages12
JournalJournal of Lipid Research
Volume54
Issue number2
DOIs
StatePublished - Feb 2013

Keywords

  • Cell migration
  • Dihydroxyeicosatrienoic acid
  • Fatty acid metabolism
  • Inflammation
  • Phospholipase A2

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

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    Kundu, S., Roome, T., Bhattacharjee, A., Carnevale, K. A., Yakubenko, V. P., Zhang, R., Hwang, S. H., Hammock, B. D., & Cathcart, M. K. (2013). Metabolic products of soluble epoxide hydrolase are essential for monocyte chemotaxis to MCP-1 in vitro and in vivo. Journal of Lipid Research, 54(2), 436-447. https://doi.org/10.1194/jlr.M031914