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The phosphatidylinositol 3-kinase signaling pathway exerts protective effects during sepsis by controlling C5a-mediated activation of innate immune functions.

Abstract
The PI3K/Akt signaling pathway has been recently suggested to have controversial functions in models of acute and chronic inflammation. Our group and others have reported previously that the complement split product C5a alters neutrophil innate immunity and cell signaling during the onset of sepsis and is involved in PI3K activation. We report in this study that in vivo inhibition of the PI3K pathway resulted in increased mortality in septic mice accompanied by strongly elevated serum levels of TNF-alpha, IL-6, MCP-1, and IL-10 during sepsis as well as decreased oxidative burst activity in blood phagocytes. PI3K inhibition in vitro resulted in significant increases in TLR-4-mediated generation of various proinflammatory cytokines in neutrophils, whereas the opposite effect was observed in PBMC. Oxidative burst and phagocytosis activity was significantly attenuated in both neutrophils and monocytes when PI3K activation was blocked. In addition, PI3K inhibition resulted in strongly elevated TLR-4-mediated generation of IL-1beta and IL-8 in neutrophils when these cells were co-stimulated with C5a. C5a-induced priming effects on neutrophil and monocyte oxidative burst activity as well as C5a-induced phagocytosis in neutrophils were strongly reduced when PI3K activation was blocked. Our data suggest that the PI3K/Akt signaling pathway controls various C5a-mediated effects on neutrophil and monocyte innate immunity and exerts an overall protective effect during experimental sepsis.
AuthorsChristiane D Wrann, Navid A Tabriz, Tanja Barkhausen, Andreas Klos, Martijn van Griensven, Hans C Pape, Daniel O Kendoff, Renfeng Guo, Peter A Ward, Christian Krettek, Niels C Riedemann
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 178 Issue 9 Pg. 5940-8 (May 01 2007) ISSN: 0022-1767 [Print] United States
PMID17442978 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cytokines
  • Lipopolysaccharides
  • Phosphoinositide-3 Kinase Inhibitors
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Complement C5a
  • Proto-Oncogene Proteins c-akt
Topics
  • Animals
  • Complement C5a (pharmacology, physiology)
  • Cytokines (blood)
  • Humans
  • Immunity, Innate
  • Lipopolysaccharides (immunology, pharmacology)
  • Mice
  • Monocytes (enzymology, immunology)
  • Neutrophils (drug effects, enzymology, immunology)
  • Phagocytes (immunology)
  • Phagocytosis
  • Phosphatidylinositol 3-Kinases (physiology)
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt (antagonists & inhibitors, physiology)
  • Respiratory Burst
  • Sepsis (immunology)
  • Signal Transduction
  • Toll-Like Receptor 4 (physiology)

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