Different functional aspects of the group II subfamily (types IIA and V) and type X secretory phospholipase A₂s in regulating arachidonic acid release and prostaglandin generation. Implications of cyclooxygenase-2 induction and phospholipid scramblase-mediated cellular membrane perturbation

We have recently reported that members of the heparin-binding group II subfamily of secretory PLA₂s (sPLA₂s) (types IIA and V), when transfected into 293 cells, released [³H]arachidonic acid (AA) preferentially in response to interleukin-1 (IL-1) and acted as 'signaling' PLA₂s that were functionally coupled with prostaglandin biosynthesis. Here we show that these group II subfamily sPLA₂s and the type X sPLA₂ behave in a different manner, the former being more efficiently coupled with the prostaglandin- biosynthetic pathway than the latter, in 293 transfectants. Type X sPLA₂, which bound only minimally to cell surface proteoglycans, augmented the release of both [³H]AA and [³H]oleic acid in the presence of serum but not IL-1. Both types IIA and V sPLA₂, the AA released by which was efficiently converted to prostaglandin E₂, markedly augmented IL-1-induced expression of cyclooxygenase (COX)-2 in a heparin-sensitive fashion, whereas type X sPLA₂ lacked the ability to augment COX-2 expression, thereby exhibiting the poor prostaglandin E₂-biosynthetic response unless either of the COX isozymes was forcibly introduced into type X sPLA₂-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, sPLA₂, releasing both [³H]AA and [³]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 sPLA₂s, 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, sPLA₂ and phospholipid scramblase resulted in a marked reduction in cell growth, revealing an unexplored antiproliferative aspect of particular classes of sPLA₂.