- 作者: 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 and Ching-Hua Hsieh
- 中文摘要: --
- 英文摘要:
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??g LPS from Escherichia coli serotype 026:B6 after 7 d was 100%, 10%, and 10%, respectively. In contrast, no mortality was noted after 500-?g 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-?B activation but an increased Akt phosphorylation in the lung and liver, when compared to that of the C57BL/6 mice. Injection of 500??g 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-?g LPS injection. In addition, the serum IL-1? and IL-2 levels were more elevated in C57BL/6 mice than in Tlr4 -/- mice. Notably, IL-1? 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. - 中文關鍵字: --
- 英文關鍵字: Lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4), Phosphoinositide 3-kinase (PI3K)