Regulatory role of C5a on macrophage migration inhibitory factor release from neutrophils.
There is evidence that C5a and macrophage migration inhibitory factor (MIF) both play important roles in experimental sepsis. Humans with sepsis also show elevated levels of both mediators in the blood. Regulation of MIF during sepsis is poorly understood. We now demonstrate that neutrophil depletion greatly reduced serum MIF levels in rats and mice during the onset of sepsis after cecal ligation and puncture. In vitro, C5a induced MIF release from rat and mouse neutrophils. In vivo blockade of C5aR or absence of C5aR led to significantly reduced MIF generation during the onset of sepsis. C5a-induced release in vitro of MIF from neutrophils appeared to be due to up-regulation of MIF in cytoplasmic granules of neutrophils via activation of the protein kinase B signaling pathway together with involvement of PI3K. Our data suggest that C5a plays a role in enhancing MIF release from neutrophils in vitro and during sepsis. These findings represent a previously unrecognized function of C5a and neutrophils in the appearance of MIF in sepsis.
Riedemann
Niels C
NC
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Guo
Ren-Feng
RF
Gao
Hongwei
H
Sun
Lei
L
Hoesel
Marco
M
Hollmann
Travis J
TJ
Wetsel
Rick A
RA
Zetoune
Firas S
FS
Ward
Peter A
PA
D000818:Animals; D015936:Complement C5a / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000378:metabolism*; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018805:Sepsis / Q000378:metabolism
D015936:Complement C5a; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt