Regulation of extracellular phospholipase A2 activity: implications for inflammatory diseases.

Phospholipases A2 (PLA2s; E.C.3.1.1.4) are a family of esterases that are involved in myriads of physiological and pathological processes. The involvement of these enzymes, especially the extracellular PLA2s, in the generation of proinflammatory lipid mediators makes them a very important target for investigation. These PLA2s have been suggested to be involved in the pathogenesis of several human inflammatory diseases. Thus, delineating the mechanism(s) of regulation of the activity of these enzymes may provide a better understanding of the pathophysiology of these diseases and allow the rational design and development of novel therapeutic agents. In this article, we provide a brief description of PLA2s in general with a special emphasis on extracellular enzymes, their mechanism(s) of action, and possible role in the pathogenesis of inflammatory diseases. Additionally, we describe: (i) a novel mechanism of activation of extracellular PLA2s by transglutaminases and (ii) the development of one class of antiinflammatory agents, antiflammins, derived from the active site structure of endogenous PLA2-inhibitory proteins.