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LGK974 suppresses lipopolysaccharide-induced endotoxemia in mice by modulating the crosstalk between the Wnt/β-catenin and NF-κB pathways

Experimental & Molecular Medicine 2021년 53권 3호 p.407 ~ 421
장재웅, 송재원, 이현지, 심인애, Kwon Young V., 조익훈, 윤유식,
소속 상세정보
장재웅 ( Jang Jae-Woong ) - Chung-Ang University College of Medicine Department of Microbiology
송재원 ( Song Jae-Won ) - Chung-Ang University College of Medicine Department of Microbiology
이현지 ( Lee Hyun-Ji ) - Chung-Ang University College of Medicine Department of Microbiology
심인애 ( Sim In-Ae ) - Chung-Ang University College of Medicine Department of Microbiology
 ( Kwon Young V. ) - University of Washington Department of Biochemistry
조익훈 ( Jho Eek-Hoon ) - University of Seoul Department of Life Science
윤유식 ( Yoon Yoo-Sik ) - Chung-Ang University College of Medicine Department of Microbiology

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-κB signaling during endotoxemia. LGK974 treatment suppressed the activation of NF-κB signaling and cytokine expression as well as the Wnt/β-catenin pathway in the livers of endotoxemic mice. Coimmunoprecipitation of phospho-IκB and β-transducin repeat-containing protein (β-TrCP) was increased in the livers of endotoxemic mice but was reduced by LGK974 treatment. Moreover, LGK974 treatment decreased the coimmunoprecipitation and colocalization of β-catenin and NF-κB, which were elevated in the livers of endotoxemic mice. Our results reveal crosstalk between the Wnt/β-catenin and NF-κB pathways via interactions between β-TrCP and phospho-IκB and between β-catenin and NF-κB during endotoxemia. The results of this study strongly suggest that the crosstalk between the Wnt/β-catenin and NF-κB 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.

키워드

Cytokines; Sepsis

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