Enhancement of Mast Cell Survival: A Novel Function of Some Secretory Phospholipase A sub(2) Isotypes

• Published in: The Journal of immunology (1950) Vol. 167; no. 8; pp. 4161 - 4171
• Main Authors: Fonteh, AN, Marion, C R, Barham, B J, Edens, M B, Atsumi, G, Samet, J M, High, K P, Chilton, F H
• Format: Journal Article
• Language: English
• Published: 15.10.2001
• Subjects: I^KB^a protein
• ISSN: 0022-1767

This study tested the hypothesis that certain secretory phospholipase A sub(2) (sPLA sub(2)) isotypes act in a cytokine-like fashion through cell surface receptors to influence mast cell survival. Initial experiments revealed that sPLA sub(2) activity and sPLA sub(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 sub(2), prevented the loss of membrane asymmetry. Similarly, group IB prevented nucleosomal DNA fragmentation in mast cells. Providing putative products of sPLA sub(2) hydrolysis to cytokine-depleted mast cells did not influence survival. Furthermore, catalytic inactivation of sPLA sub(2) did not alter its capacity to prevent apoptosis. Inhibition of protein synthesis using cycloheximide or actinomycin reversed the antiapoptotic effect of sPLA sub(2). Additionally, both wild-type and catalytically inactive group IB PLA sub(2) induced IL-3 synthesis in mast cells. However, adding IL-3-neutralizing Ab did not change Annexin V super(FITC) binding and only partially inhibited thymidine incorporation in sPLA sub(2)-supplemented mast cells. In contrast, IL-3-neutralizing Ab inhibited both Annexin V super(FITC) binding and thymidine incorporation in mast cells maintained with IL-3. sPLA sub(2) enhanced phosphoinositide 3'-kinase activity, and a specific inhibitor of phosphoinositide 3'-kinase reversed the antiapoptotic effects of sPLA sub(2). Likewise, sPLA sub(2) increased the degradation of I- Kappa B alpha , and specific inhibitors of nuclear factor Kappa activation (NF- Kappa B) reversed the antiapoptotic effects of sPLA sub(2). Together, these experiments reveal that certain isotypes of sPLA sub(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 sub(2) receptors rather than sPLA sub(2) catalytic products.