Recent recognition of the rapidly growing sPLA2 family has led to a suggestion that some of the previously described functions of sPLA2-IIA need to be reevaluated, since studies based upon enzyme activities and using inhibitors or antibodies against sPLA2-IIA may not discriminate these sPLA2s. Our present studies reconfirm the involvement of sPLA2-IIA in biological responses, demonstrated significant crosstalk between the two Ca(2+)-dependent PLA2s (cPLA2 and sPLA2) where one enzyme is required for the induction of the other, and revealed segregated coupling of discrete PLA2 and COX enzymes in the different phases of PG biosynthesis. Based upon the analysis of cells derived from sPLA2-IIA "natural knock-out" mice, it is apparent that sPLA2-IIA is not essential for the initiation of delayed PGE2 biosynthesis. However, it is capable of contributing to the delayed response as an enhancer when appropriately induced by proinflammatory stimuli, leading to optimal COX-2-dependent PGE2 generation. Importantly, in order for sPLA2-IIA (or related sPLA2 isozymes) to attack the biological membranes, so-called "membrane rearrangement" should take place in activated, but not resting, cells. Membrane rearrangement also occurs when cells are undergoing apoptosis, during which acidic phospholipids, the preferred substrates for sPLA2-IIA, are exposed on the outer leaflet of the plasma membranes. Nonetheless, in view of the dramatically elevated levels of sPLA2-IIA in inflamed or ischemic sites, it is likely that this extracellular isozyme participates in the expansion of chronic tissue disorders by augmenting generation of proinflammatory eicosanoids or lysophospholipids, depending upon the states of the inflammatory response.