title: Metabolic products of soluble epoxide hydrolase are essential for monocyte chemotaxis to MCP-1 in vitro and in vivo.
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 A(2) (cPLA(2)). 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 cPLA(2)-deficient monocytes and monocytes with blocked Erk1/2 activity, because Erk controls cPLA(2) 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.
authors.affiliation: Department of Cell Biology, and Research Core Services, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Suman
authors.initials: S
authors.lastname: Kundu
authors.forename: Talat
authors.initials: T
authors.lastname: Roome
authors.forename: Ashish
authors.initials: A
authors.lastname: Bhattacharjee
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Carnevale
authors.forename: Valentin P
authors.initials: VP
authors.lastname: Yakubenko
authors.forename: Renliang
authors.initials: R
authors.lastname: Zhang
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Martha K
authors.initials: MK
authors.lastname: Cathcart
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000096:biosynthesis; D018932:Chemokine CCL2 / Q000378:metabolism*; D002633:Chemotaxis / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D008084:Lipoxygenase / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012995:Solubility
chemical_list: C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D054510:Phospholipases A2, Cytosolic; D004851:Epoxide Hydrolases; C572289:eicosenoic acid