Biological Functions of Group X Secretory PLA₂

Abstract

Secretory phospholipase A₂s (sPLA₂s) are a diverse family of low molecular mass enzymes that hydrolyze the sn-2 fatty acid ester bond of glycerophospholipids to produce free fatty acids and lysophospholipids. In addition to the classical types of group IB and IIA (sPLA₂-IB and IIA), recent advances in molecular biology have led to the identification of novel types of sPLA₂s, including group IID and IIE that we have cloned [1]. Among the nine types of human sPLA₂s, group X sPLA₂ (sPLA₂-X) has a structural similarity with the classical type of sPLA₂-IB and IIA [2]. We have shown that sPLA₂-X has a potent hydrolyzing activity toward phosphatidylcholine (PC) and elicits more potent production of unsaturated fatty acids and lysophosphatidylcholine (lysoPC) in various inflammatory cells and colon cancer cells compared with sPLA₂-IB and IIA [3,4]. The released arachidonic acid by sPLA₂-X was efficiently converted to prostaglandins (PGs) by the action of endogenous cyclooxygenase (COX). The expression of sPLA₂-X was detected in human lung epithelial cells and mouse splenic macrophages, and greatly augmented in human colon adenocarcinoma tissues in concert with enhanced expression of COX-2 [4]. These findings suggest that sPLA₂-X plays a critical role in the lipid mediator productions under various inflammatory states and in the COX-2- dependent PGE₂ biosynthesis during colon tumorigenesis. Recently, we have shown that sPLA₂-X is a high-affinity ligand for mouse PLA₂ receptor (PLA₂R) and identified a soluble PLA₂R in mouse plasma [5]. Using PLA₂ receptor-deficient mice, we have shown that the membrane and soluble form of the receptor are involved in the endogenous inhibitory mechanisms against the strong PC-hydrolizing activity of sPLA₂-X in mice [5].