C5a delays apoptosis of human neutrophils by a phosphatidylinositol 3-kinase-signaling pathway.

Abstract

BACKGROUND Studies have shown that survival factors including cytokines and growth factors delay apoptosis of human neutrophils via induction of the phosphatidylinositol-3 kinase (PI 3-K)/Akt pathway. In the present study, we explored whether complement fragment C5a has a modulatory effect on neutrophil apoptosis through this signaling pathway. METHODS Human neutrophils were isolated and treated with C5a for up to 24 hours, with or without wortmannin, a PI 3-K inhibitor, and staurosporine, a caspase-9 activator. Apoptosis was quantified by flow cytometry, using propidium iodide nuclear staining, and confirmed by the detection of DNA fragmentation on gel electrophoresis. PI 3-K downstream signaling events were evaluated by measuring the expression of cytosolic total and phosphorylated Akt and Bad proteins by Western blot analyses, and caspase-9 activity. RESULTS C5a inhibited neutrophil apoptosis in a dose- and time-dependent manner. The anti-apoptotic effects of C5a were markedly abrogated in the presence of wortmannin. Brief stimulation of neutrophils with C5a induced phosphorylation of Akt and Bad proteins through a PI 3-K-dependent pathway. Caspase-9 activity was minimal in C5a-treated cells, but markedly increased following PI 3-K inhibition by wortmannin. Finally, C5a reduced caspase-9 activity in staurosporine-treated cells. CONCLUSIONS This study demonstrates that C5a inhibits neutrophil apoptosis via a PI 3-K signaling pathway. This effect may be an important mechanism that improves cell survival and function in the inflammatory milieu.

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@article{Perianayagam2002C5aDA, title={C5a delays apoptosis of human neutrophils by a phosphatidylinositol 3-kinase-signaling pathway.}, author={Mary C. Perianayagam and V. S. Balakrishnan and Andrew J. King and Brian J. G. Pereira and Bertrand L. Jaber}, journal={Kidney international}, year={2002}, volume={61 2}, pages={456-63} }