The phosphatidylinositol 3 kinase pathway regulates tolerance to lipopolysaccharide and priming responses to Staphylococcus aureus and lipopolysaccharide.
Our previous studies have demonstrated that although LPS and Staphylococcus aureus induce homologous tolerance, they induce priming to each other instead of cross-tolerance. The phosphatidylinositol 3 (PI3) kinase pathway has been implicated in microbial signaling and inflammatory gene expression regulation. We hypothesized that LPS or S. aureus induced tolerance and priming responses to each other are PI3 kinase pathway-dependent. CD1 mice received intraperitoneal injections of 1% Biogel and were treated intraperitoneally with vehicle, LPS, or S. aureus (5 mg/kg) 3 days later. Peritoneal macrophages (MØ) were harvested 24 h later and exposed to vehicle or the PI3 kinase inhibitors wortmannin (10 nmol/L) or LY294002 (10 nmol/L) 1 h before in vitro stimulation with LPS or S. aureus (10 microg/mL). Both LPS and S. aureus significantly induced tumor necrosis factor alpha and thromboxane B2 synthesis (P < 0.05, n = 3) in naive cells. LPS and S. aureus induced homologous tolerance were associated with suppressed tumor necrosis factor alpha and thromboxane B2 levels but augmented interleukin 10 production. However, LPS and S. aureus induced priming to each other, as shown by augmented mediator production. Wortmannin and LY294002 reversed LPS tolerance yet had no effect on S. aureus tolerance. PI3 kinase blockade attenuated the priming responses to both LPS and S. aureus. Mice pretreated with LPS and challenged with LPS were protected. In contrast, mice pretreated with LPS and wortmannin demonstrated LPS tolerance reversal. These data suggest that PI3 kinase is essential for LPS induced homologous tolerance and reciprocal LPS and S. aureus induced priming responses.
Peck
Octavia M
OM
Department of Neurosciences, The Medical University of South Carolina, Charleston, SC 29425, USA.
Zingarelli
Basilia
B
Fan
Hongkuan
H
Teti
Giuseppe
G
Tempel
George
G
Halushka
Perry V
PV
Cook
James A
JA
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000201:enzymology*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013211:Staphylococcus aureus; D013929:Thromboxane B2 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D008070:Lipopolysaccharides; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D013929:Thromboxane B2; D014409:Tumor Necrosis Factor-alpha; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one