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Kidney Int. 2002 Feb;61(2):456-63.

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

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Division of Nephrology, Department of Medicine, Tupper Research Institute, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA.



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.


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.


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.


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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