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

Johnson Chia Shen Yang, Shao Chun Wu, Cheng Shyuan Rau, Tsu Hsiang Lu, Yi Chan Wu, Yi Chun Chen, Ming Wei Lin, Siou Ling Tzeng, Chia Jung Wu, Ching Hua Hsieh*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

13 Scopus citations

Abstract

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.

Original languageEnglish
Article number20
JournalJournal of Biomedical Science
Volume21
Issue number1
DOIs
StatePublished - 11 03 2014

Keywords

  • Lipopolysaccharide (LPS)
  • Phosphoinositide 3-kinase (PI3K)
  • Toll-like receptor 4 (TLR4)

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