The Phosphatidylinositol 3 Kinase Pathway Regulates Tolerance to Lipopolysaccharide and Priming Responses to Staphylococcus Aureus and Lipopolysaccharide

Abstract

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.

Macrophage tolerance response to Aggregatibacter actinomycetemcomitans lipopolysaccharide induces differential regulation of tumor necrosis factor‐α, interleukin‐1β and matrix metalloproteinase 9 secretion

“…The decreased secretion of mediators associated with the tolerance phenomenon has been linked to alterations in signal events (14,28). Phosphatidylinositol‐3′‐kinase, an enzyme complex, regulates a pathway involved in the expression of various lipopolysaccharide‐induced inflammatory genes and lipopolysaccharide tolerance (28,29). It behaves as an early inhibitor of Toll‐like receptor signaling (30).…”

Erythropoietin mediates re-programming of endotoxin-tolerant macrophages through PI3K/AKT signaling and protects mice against secondary infection

“…In accordance with our observations, there have been increasing studies indicating that PI3K/AKT pathway is essential for LPS-induced tolerance. For example, it has been reported that blockade of PI3K with its inhibitor wortmannin reversed in vivo tolerance in LPS-pretreated mice ( 48 , 49 ). For another example, results from Pik3r1 −/− -deficient mice (PI3K activity reduced) and PTEN −/− mice (AKT activity enhanced) demonstrated that PI3K/AKT pathway negatively regulated LPS signaling in macrophages and endotoxemic mice ( 50 ).…”

Lysophosphatidic Acid Inhibits Bacterial Endotoxin-Induced Pro-Inflammatory Response: Potential Anti-Inflammatory Signaling Pathways

“…Guha and Mackman have reported that activation of the PI3 kinase/Akt signaling pathway limits the pro-inflammatory effects of LPS in cultured monocytes (17). Our recent studies demonstrated PI3 kinase inhibitor, wortmannin, and LY294002 abolished the protective effect of endotoxin tolerance (41). Numerous studies have demonstrated that LPA can activate the PI3 kinase signaling pathway (42)(43)(44)(45).…”