Mammalian secreted phospholipases A2 and their pathophysiological significance in inflammatory diseases

Abstract

Phospholipases A2 (PLA2s) represent a growing family of enzymes that catalyze the hydrolysis of phospholipids at the sn-2 position leading to the generation of free fatty acids and lysophospholipids. Mammalian PLA2s are divided into two major classes according to their molecular mass and location: intracellular PLA2 and secreted PLA2 (sPLA2). Type-IIA sPLA2 (sPLA2-IIA), the best studied enzyme of sPLA2, plays a role in the pathogenesis of various inflammatory diseases. Conversely, sPLA2-IIA can exert beneficial action in the context of infectious diseases since recent studies have shown that this enzyme exhibits potent bactericidal effects. Induction of the synthesis of sPLA2-IIA is generally initiated by endotoxin and a limited number of cytokines via paracrine and/or autocrine processes. If the mechanisms involved in the regulation of sPLA2-IIA gene expression have been relatively clarified, little is known on the mechanisms that regulate the expression of other sPLA2. There have been substantial progresses in understanding the transcriptional regulation of sPLA2-IIA expression. Recently, transcription factors including NF-kappaB, PPAR, C/EBP have been identified to play a prominent role in the regulation of sPLA2-IIA gene expression. The activation of these transcription factors is under the control of distinct signaling pathways (PKC, cAMP ...). Accumulating evidences in the literature suggest that cytosolic PLA2 together with two sPLA2 isozymes (sPLA2-IIA and sPLA2-V) are functionally coupled with cyclooxygenase-1 and 2 pathways, respectively, for immediate and delayed PG biosynthesis. This spatio-temporal coupling of cyclooxygenase enzymes with PLA2s may represent a key mechanism in the propagation of inflammatory reaction. Unraveling the mechanisms involved in the regulation of the expression of sPLA2s is important for understanding their pathophysiological roles in inflammatory diseases.