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Background  Upon lipopolysaccharide (LPS) stimulation, activation of both the Toll-like receptor 4 (TLR4) and phosphoinositide 3-kinase (PI3K) pathways serves to balance proinflammatory and anti-inflammatory responses. Although the antagonist to TLR4 represents an emerging promising target for the treatment of sepsis; however, the role of the PI3K pathway under TLR4-null conditions is not well understood. This goal of this study was to investigate the effect of inhibition of PI3K on innate resistance to LPS toxicity in a murine model.    Results  The overall survival of the cohorts receiving intraperitoneal injections of 100, 500, or 1000 μg LPS from  Escherichia coli  serotype 026:B6 after 7 d was 100%, 10%, and 10%, respectively. In contrast, no mortality was noted after 500-μg LPS injection in  Tlr4  -/-  mice. When the PI3K inhibitor LY294002 was injected (1 mg/25 g body weight) 1 h prior to the administration of LPS, the overall survival of the  Tlr4  -/-  mice was 30%. In the  Tlr4  -/-  mice, the LPS injection induced no NF-κB activation but an increased Akt phosphorylation in the lung and liver, when compared to that of the C57BL/6 mice. Injection of 500 μg LPS led to a significant induction in O 2  -  detected by electron paramagnetic resonance (EPR) spin trapping spectroscopy in the lung and liver at 3 and 6 h in C57BL/6 but not  Tlr4  -/-  mice. Addition of LY294002 only significantly increased the O 2  -  level in the lung and liver of the  Tlr4  -/-  mice but not in the C57BL/6 mice following 500-μg LPS injection. In addition, the serum IL-1β and IL-2 levels were more elevated in C57BL/6 mice than in  Tlr4  -/-  mice. Notably, IL-1β and IL-2 were significantly increased in  Tlr4  -/-  mice but not in the C57BL/6 mice when the PI3K pathway was inhibited by LY294002 prior to LPS injection.    Conclusions  In this study, we demonstrate that innate resistance to LPS toxicity in  Tlr4  -/-  mice is impaired by inhibition of the PI3K pathway, with a corresponding increase in mortality and production of tissue O 2  -  and inflammatory cytokines.

Inhibition of the phosphoinositide 3-kinase pathway decreases innate resistance to lipopolysaccharide toxicity in TLR4 deficient mice