LGK974 suppresses lipopolysaccharide-induced endotoxemia in mice by modulating the crosstalk between the Wnt/beta-catenin and NF-kappa B pathways

Abstract

Endotoxemia, a type of sepsis caused by gram-negative bacterial endotoxin [i.e., lipopolysaccharide (LPS)], is associated with manifestations such as cytokine storm; failure of multiple organs, including the liver; and a high mortality rate. We investigated the effect and mechanism of action of LGK974, a Wnt signaling inhibitor, in mice with LPS-induced endotoxemia, an animal model of sepsis. LGK974 significantly and dose-dependently increased the survival rate and reduced plasma cytokine levels in mice with LPS-induced endotoxemia. Transcriptome analysis of liver tissues revealed significant changes in the expression of genes associated with the Wnt pathway as well as cytokine and NF-kappa B signaling during endotoxemia. LGK974 treatment suppressed the activation of NF-kappa B signaling and cytokine expression as well as the Wnt/beta-catenin pathway in the livers of endotoxemic mice. Coimmunoprecipitation of phospho-I kappa B and beta-transducin repeat-containing protein (beta-TrCP) was increased in the livers of endotoxemic mice but was reduced by LGK974 treatment. Moreover, LGK974 treatment decreased the coimmunoprecipitation and colocalization of beta-catenin and NF-kappa B, which were elevated in the livers of endotoxemic mice. Our results reveal crosstalk between the Wnt/beta-catenin and NF-kappa B pathways via interactions between beta-TrCP and phospho-I kappa B and between beta-catenin and NF-kappa B during endotoxemia. The results of this study strongly suggest that the crosstalk between the Wnt/beta-catenin and NF-kappa B pathways contributes to the mutual activation of these two pathways during endotoxemia, which results in amplified cytokine production, liver damage and death, and that LGK974 suppresses this vicious amplification cycle by reducing the crosstalk between these two pathways. Inflammation: Stopping the out-of-control spiral A cancer drug called LGK974 may help treat sepsis, an exaggerated inflammatory response to infection leading to multiple organ failure and a leading cause of death in patients in intensive care. Sepsis can result when the body's response to infection spirals out of control. Although the mechanism is poorly understood, the Wnt signaling pathway was recently reported to be involved. Yoosik Yoon at Chung-Ang University College of Medicine and Eek-hoon Jho at the University of Seoul, both in South Korea, investigated how LGK974, developed to fight cancers dependent on Wnt signaling, would affect sepsis, using a mouse model. They discovered that LGK974 interrupted feedback between Wnt and another signaling pathway, preventing uncontrolled amplification of inflammation. The mice showed decreased organ damage and increased survival. These results present a promising research direction for treating sepsis.