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

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 o2 - 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 o2 - 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 o2 - and inflammatory cytokines. © 2014 yang et al.; licensee biomed central ltd.