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Enhancement of Mast Cell Survival: A Novel Function of Some Secretory Phospholipase A₂ Isotypes¹

Alfred N. Fonteh^2,*, Chad R. Marion^*, Brooke J. Barham^*, Michelle B. Edens^*, Gen-ichi Atsumi, James M. Samet, Kevin P. High and Floyd H. Chilton^*,

^* Department of Internal Medicine, Section on Pulmonary and Critical Care Medicine, Divisions of Infectious Diseases, and Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157; and Human Studies Division, National Health and Environmental Effects Research Laboratory, Chapel Hill, NC 27599

This study tested the hypothesis that certain secretory phospholipase A₂ (sPLA₂) isotypes act in a cytokine-like fashion through cell surface receptors to influence mast cell survival. Initial experiments revealed that sPLA₂ activity and sPLA₂ 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 PLA₂, prevented the loss of membrane asymmetry. Similarly, group IB prevented nucleosomal DNA fragmentation in mast cells. Providing putative products of sPLA₂ hydrolysis to cytokine-depleted mast cells did not influence survival. Furthermore, catalytic inactivation of sPLA₂ did not alter its capacity to prevent apoptosis. Inhibition of protein synthesis using cycloheximide or actinomycin reversed the antiapoptotic effect of sPLA₂. Additionally, both wild-type and catalytically inactive group IB PLA₂ 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 sPLA₂-supplemented mast cells. In contrast, IL-3-neutralizing Ab inhibited both Annexin V^FITC binding and thymidine incorporation in mast cells maintained with IL-3. sPLA₂ enhanced phosphoinositide 3'-kinase activity, and a specific inhibitor of phosphoinositide 3'-kinase reversed the antiapoptotic effects of sPLA₂. Likewise, sPLA₂ increased the degradation of I-B, and specific inhibitors of nuclear factor activation (NF-B) reversed the antiapoptotic effects of sPLA₂. Together, these experiments reveal that certain isotypes of sPLA₂ enhance the survival of mast cells in a cytokine-like fashion by activating antiapoptotic signaling pathways independent of IL-3 and probably via sPLA₂ receptors rather than sPLA₂ catalytic products.

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