PI3K-Akt pathway suppresses coagulation and inflammation in endotoxemic mice.
OBJECTIVE
In endotoxemia, lipopolysaccharide (LPS) induces a systemic inflammatory response and intravascular coagulation. Monocytes orchestrate the innate immune response to LPS by expressing a variety of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), and the procoagulant molecule, tissue factor (TF). In this study, we analyzed the role of the phosphoinositide 3-kinase (PI3K)-Akt pathway in the activation of coagulation and the innate immune response in a mouse model of endotoxemia.


RESULTS
Wortmannin and LY294002 were used to inhibit the PI3K-Akt pathway. We found that wortmannin inhibited LPS-induced Akt phosphorylation in blood cells. Inhibition of the PI3K-Akt pathway significantly increased TF mRNA expression in blood cells, TF antigen, and thrombin-antithrombin III levels in the plasma, and fibrin deposition in the liver of endotoxemic mice. Inhibition of the PI3K-Akt pathway also strongly enhanced LPS-induced cytokine expression and the levels of soluble E-selectin in the plasma, suggesting enhanced activation of both monocytes and endothelial cells. Wortmannin treatment also increased the number of macrophages in the liver and kidney of endotoxemic mice. Finally, wortmannin and LY294002 dramatically reduced the survival time of endotoxemic mice.


CONCLUSIONS
These data suggest that the PI3K-Akt pathway suppresses LPS-induced inflammation and coagulation in endotoxemic mice.
Department of Immunology, The Scripps Research Institute, La Jolla, Calif 92037, USA.
Gernot
G
Schabbauer
Michael
M
Tencati
Brian
B
Pedersen
Rafal
R
Pawlinski
Nigel
N
Mackman
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001777:Blood Coagulation / Q000502:physiology*; D018925:Chemokines / Q000378:metabolism / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism / Q000502:physiology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D019446:Endotoxemia / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000473:pathology; D008262:Macrophage Activation / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology; D000077191:Wortmannin
D000730:Androstadienes; D018925:Chemokines; D002867:Chromones; D016207:Cytokines; D008070:Lipopolysaccharides; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human