Basic Immunology
Caspase-1 aggravates the D-galactosamine/lipopolysaccharide induced acute liver failure in mice through activating glycogen synthase kinase-3β
Rongrong Yang, Feng Ren, Li Zhang, Xiangying Zhang, Hongbo Shi, Dexi Chen, Zhongping Duan, Qi Wang
Published 2016-02-29
Cite as Chin J Microbiol Immunol, 2016, 36(2): 132-137. DOI: 10.3760/cma.j.issn.0254-5101.2016.02.010
Abstract
ObjectiveTo analyze the role of cysteinyl aspartate specific proteinase-1 (caspase-1) in a mouse model of D-galactosamine (D-GalN) and lipopolysaccharide (LPS) induced acute liver failure (ALF) and to study the possible mechanism.
MethodsC57BL/6 mice were randomly divided into four groups including control group, Z-WEHD-FMK (caspase-1 inhibitor) treatment group, ALF model group and Z-WEHD-FMK-treated ALF group. The mouse model of ALF was established by intraperitoneally injecting the mice with D-GalN (450 mg/kg) and LPS (10 μg/kg). The damages in liver tissues were evaluated based on the histopathological examination and the levels of alanine transaminase (ALT) and aspartate transaminase (AST) in serum samples. Western blot assay was performed to analyze the expression of caspase-1 and the phosphorylation of glycogen synthase kinase 3β (GSK-3β). The qRT-PCR was used to measure the expression of inflammatory cytokines at transcriptional level.
ResultsThe expression of caspase-1 at both mRNA and protein levels were gradually increased during the development of ALF. Compared with the mice with ALF, those in the Z-WEHD-FMK-treated ALF group showed less severe liver damages on histopathological examination and decreased levels of ALT and AST in serum samples [ALT: (479.2±39.5) U/L vs (998.5±60.4 ) U/L, P<0.05; AST: ( 478.5±28.6) U/L vs ( 1 180.7±91.4) U/L, P<0.05]. The expression of TNF-α, IL-1β, IL-18 and IL-33 at transcriptional level were significantly suppressed in mice with ALF upon the Z-WEHD-FMK intervention. Results of the Western blot assay indicated that Z-WEHD-FMK suppressed the activities of GSK-3β by enhancing its phosphorylation.
ConclusionThis study demonstrated that caspase-1 could promote the activation of GSK-3β resulting in the development of inflammation responses and liver damages during the development of ALF in mice.
Key words:
Caspase-1; Glycogen synthase kinase-3β; Liver failure; Acute; Inflammation
Contributor Information
Rongrong Yang
Department of Gastroenterology, the Second Hospital of Shanxi Medical University, Taiyuan 030001, China
Feng Ren
Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
Li Zhang
Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
Xiangying Zhang
Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
Hongbo Shi
Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
Dexi Chen
Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
Zhongping Duan
Artificial Liver Treatment &
Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
Qi Wang
Department of Gastroenterology, the Second Hospital of Shanxi Medical University, Taiyuan 030001, China
