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We have recently reported that members of the heparin-binding group II subfamily of secretory PLA 2 s (sPLA 2 s) (types IIA and V), when transfected into 293 cells, released [ 3 H]arachidonic acid (AA) preferentially in response to interleukin-1 (IL-1) and acted as "signaling" PLA 2 s that were functionally coupled with prostaglandin biosynthesis. Here we show that these group II subfamily sPLA 2 s and the type X sPLA 2 behave in a different manner, the former being more efficiently coupled with the prostaglandin-biosynthetic pathway than the latter, in 293 transfectants. Type X sPLA 2 , which bound only minimally to cell surface proteoglycans, augmented the release of both [ 3 H]AA and [ 3 H]oleic acid in the presence of serum but not IL-1. Both types IIA and V sPLA 2 , the AA released by which was efficiently converted to prostaglandin E 2 , markedly augmented IL-1-induced expression of cyclooxygenase (COX)-2 in a heparin-sensitive fashion, whereas type X sPLA 2 lacked the ability to augment COX-2 expression, thereby exhibiting the poor prostaglandin E 2 -biosynthetic response unless either of the COX isozymes was forcibly introduced into type X sPLA 2 -expressing cells. Implication of phospholipid scramblase, an enzyme responsible for the perturbation of plasma membrane asymmetry, revealed that the scramblase-transfected cells became more sensitive to types IIA and V, but not X, sPLA 2 , releasing both [ 3 H]AA and [ 3 H]oleic acid in an IL-1-independent manner. Thus, although phospholipid scramblase-mediated alteration in plasma membrane asymmetry actually led to the increased cellular susceptibility to the group II subfamily of sPLA 2 s, several lines of evidence suggest that it does not entirely mimic their actions on cells after IL-1 signaling. Interestingly, coexpression of type IIA or V, but not X, sPLA 2 and phospholipid scramblase resulted in a marked reduction in cell growth, revealing an unexplored antiproliferative aspect of particular classes of sPLA 2 .