In vivo regulation of neutrophil apoptosis by C5a during sepsis.
Delayed neutrophil apoptosis is characteristic of sepsis and may accentuate organ injury. It has been shown that PI-3K 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 with 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 abrogated completely by inhibition of PI-3K and partially diminished by 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 cecal ligation and puncture rats by anti-C5a antibody markedly restored the susceptibility of neutrophils to undergo apoptosis. C5a activated AKT and p44/42 and also enhanced X-linked inhibitor of apoptosis expression in neutrophils. 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 PI-3K, increased antiapoptotic protein expression, and ultimately, delayed neutrophil apoptosis.
Guo
Ren-Feng
RF
University of Michigan Medical School, Department of Pathology, 1301 Catherine Road, Ann Arbor, MI 48109-0602, USA. grf@med.umich.edu
Sun
Lei
L
Gao
Hongwei
H
Shi
Kevin X
KX
Rittirsch
Daniel
D
Sarma
Vidya J
VJ
Zetoune
Firas S
FS
Ward
Peter A
PA
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D020169:Caspases / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D018805:Sepsis / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000276:immunology / Q000378:metabolism; D051020:bcl-X Protein / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D008070:Lipopolysaccharides; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; D015936:Complement C5a; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases