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Regulation of C5a on Neutrophil Apoptosis During Sepsis
Author(s) -
Guo RenFeng,
Sun Lei,
Gao Hongwei,
Reuben Jayne S,
Shi Kevin X,
Sarma J Vidya,
Zetoune Firas S,
Ward Peter A
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a644
Subject(s) - apoptosis , xiap , protein kinase b , sepsis , kinase , signal transduction , immunology , mapk/erk pathway , microbiology and biotechnology , biology , programmed cell death , caspase , biochemistry
Delayed neutrophil apoptosis is characteristic of sepsis and may accentuate organ injury. It has been shown that phosphatidylinositol 3‐kinase (PI3‐K) and MAPK pathways provide survival signaling in neutrophils. In this study, we demonstrate that neutrophils isolated from septic rats are resistant to apoptosis in comparison to the cells from normal animals. In contrast to normal serum, septic sera induced strong phosphorylation of AKT and p44/42 in neutrophils obtained from normal rats, resulting in marked resistance of these cells to apoptosis. Protection from apoptosis by septic sera was completely abrogated by inhibition of PI3‐K and partially diminished by MAP kinase (MEK) inhibition. Increased neutrophil survival in septic rats was associated with increased levels of Bcl‐xL in neutrophils and decreased levels of Bim expression. In vivo blockade of C5a in CLP rats by anti‐C5a antibody markedly restored the susceptibility of neutrophils to undergo apoptosis. C5a activated AKT and p44/42, and also enhanced XIAP expression in neutrophils. This enhancement was further augmented by LPS co‐stimulation. Both LPS and C5a were able to induce Bcl‐xL expression. Thus, neutrophil survival signals derived from effects of septic sera could be linked to activation of ERK1/2 and PI3‐K, increased anti‐apoptotic protein expression, and ultimately delayed neutrophil apoptosis. This work is supported by NIH grants GM‐61656, GM‐29507 and HL‐31963.