Abstract

2-Arachidonyl-lysophosphatidylethanolamine, shortly 2-ARA-LPE, is a polyunsaturated lysophosphatidylethanolamine. 2-ARA-LPE has a very long chain arachidonic acid, formed by an ester bond at the sn-2 position. It has been reported that 2-ARA-LPE has anti-inflammatory effects in a zymosan-induced peritonitis model. However, it’s action mechanisms are poorly investigated. Recently, resolution of inflammation is considered to be an active process driven by M2 polarized macrophages. Therefore, we have investigated whether 2-ARA-LPE acts on macrophages for anti-inflammation, whether 2-ARA-LPE modulates macrophage phenotypes to reduce inflammation, and whether 2-ARA-LPE is anti-inflammatory in a carrageenan-induced paw edema model. In mouse peritoneal macrophages, 2-ARA-LPE was found to inhibit lipopolysaccharide (LPS)-induced M1 macrophage polarization, but not induce M2 polarization. 2-ARA-LPE inhibited the inductions of inducible nitric oxide synthase and cyclooxygenase-2 in mouse peritoneal macrophages at the mRNA and protein levels. Furthermore, products of the two genes, nitric oxide and prostaglandin E2, were also inhibited by 2-ARA-LPE. However, 1-oleoyl-LPE did not show any activity on the macrophage polarization and inflammatory responses. The anti-inflammatory activity of 2-ARA-LPE was also verified in vivo in a carrageenan-induced paw edema model. 2-ARA-LPE inhibits LPS-induced M1 polarization, which contributes to anti-inflammation and suppresses the carrageenan-induced paw edema in vivo.

Highlights

  • Lysophosphatidic acid is a representative lyso-type intercellular mediator that acts through G protein-coupled receptors (LPA1-6 ) [1]

  • We have studied effects of long-chain LPEs such as 1-oleoyl LPE (1-OLELPE), 1-palmitoyl LPE, and 1-myristoyl LPE on intracellular Ca2+ ([Ca2+ ]i ) increasing actions in PC-12 and SH-SY5Y neuronal cells, and SK-OV3 ovarian and MDA-MB-231 breast cancer cells [4,5,6,7]. These studies elucidated that LPE-induced [Ca2+ ]i responses have common and dissimilar characteristics among cell types; that is, LPA1 involvement is common to PC-12, SH-SY5Y, and MDA-MB-231 cells, but differs in SK-OV3 cells, whereas responses to different LPE structural types differed in the cell lines

  • Plasma levels of polyunsaturated long chain LPEs including 22:6 LPE, 20:4 LPE, and 18:2 LPE were increased about three-fold in acute coronary syndrome subjects compared to levels in patients with normal coronary arteries [8]

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Summary

Introduction

Lysophosphatidic acid is a representative lyso-type intercellular mediator that acts through G protein-coupled receptors (LPA1-6 ) [1]. We have studied effects of long-chain LPEs such as 1-oleoyl LPE (1-OLELPE), 1-palmitoyl LPE, and 1-myristoyl LPE on intracellular Ca2+ ([Ca2+ ]i ) increasing actions in PC-12 and SH-SY5Y neuronal cells, and SK-OV3 ovarian and MDA-MB-231 breast cancer cells [4,5,6,7]. These studies elucidated that LPE-induced [Ca2+ ]i responses have common and dissimilar characteristics among cell types; that is, LPA1 involvement is common to PC-12, SH-SY5Y, and MDA-MB-231 cells, but differs in SK-OV3 cells, whereas responses to different LPE structural types differed in the cell lines. Plasma levels of polyunsaturated long chain LPEs including 22:6 LPE, 20:4 LPE, and 18:2 LPE were increased about three-fold in acute coronary

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