Enhancement of mast cell survival: A novel function of some secretory phospholipase A(2) isotypes

This study tested the hypothesis that certain secretory phospholipase A. (s PLA(2)) isotypes act in a cytokine-like fashion through cell surface recept ors to influence mast cell survival. Initial experiments revealed that sPLA (2) activity and sPLA(2) receptor expression are increased, and mast cells lost their capacity to maintain membrane asymmetry upon cytokine depletion. Groups IB and III, but not group IIA PLA(2), prevented the loss of membran e asymmetry. Similarly, group IB prevented nucleosomal DNA fragmentation in mast cells. Providing putative products of sPLA(2) hydrolysis to cytokine- depleted mast cells did not influence survival. Furthermore, catalytic Inac tivation of sPLA(2) did not alter its capacity to prevent apoptosis. Inhibi tion of protein synthesis using cycloheximide or actinomycin reversed the a ntiapoptotic effect of sPLA(2). Additionally, both wild-type and catalytica lly inactive group IB PLA(2) induced IL-3 synthesis in mast cells. However, adding IL-3-neutralizing Ab did not change Annexin V-FITC binding and only partially inhibited thymidine incorporation in sPLA(2)-supplemented mast c ells. In contrast, IL-3-neutralizing Ab inhibited both Annexin V-FITC bindi ng and thymidine incorporation in mast cells maintained with IL-3. sPLA(2) enhanced phosphoinositide 3 ' -kinase activity, and a specific inhibitor of phosphoinositide 3 ' -kinase reversed the antiapoptotic effects of sPLA(2) . Likewise, sPLA(2) increased the degradation of I-kappaB alpha, and specif ic inhibitors of nuclear factor x activation (NF-kappaB) reversed the antia poptotic effects of sPLA(2). Together, these experiments reveal that certai n isotypes of sPLA(2) enhance the survival of mast cells in a cytokine-like fashion by activating antiapoptotic signaling pathways independent of IL-3 and probably via sPLA(2) receptors rather than sPLA(2) catalytic products.