Toll-Like Receptor 4-Dependent CCAAT-Enhancer-Binding Protein Homologous Protein Activation Induces Hepatocellular Cell Death in Liver Ischemia and Reperfusion Injury.
1Department of Liver Surgery, First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
2Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
Meeting: 2017 American Transplant Congress
Abstract number: C123
Session Information
Session Name: Poster Session C: Innate Immunity
Session Type: Poster Session
Date: Monday, May 1, 2017
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall D1
Background: Critical role of Toll-like receptor 4(TLR4) and endoplasmic reticulum (ER) stress has been found in ischemia and reperfusion(IR) injury models. However, the relationship between TLR4 and ER stress during liver IR injury still remains unclear.
Methods: Wild-type(WT), TLR4 knockout(TLR4 KO) and CCAAT-Enhancer-Binding Protein Homologous Protein knockout (CHOP KO) mice were subjected to a murine liver partial warm ischemia model. Liver injury and hepatocellular cell death was compared between groups. In vitro, cell death of primary hepatocytes isolated from WT, TLR4 KO and CHOP KO mice was induced and evaluated. Intracellular cell death signaling pathways were analyzed by western blot in vivo and in vitro as well.
Results: Liver IR induced marked hepatocellular cell death, as indicated by HE/TUNEL staining and western blot analysis of cleaved-Caspase-3, BCL-2 and BCL-XL. Protein levels of TLR4 and CHOP were elevated by IR as well. In vitro, TLR4 and CHOP activation, accompany with cleaved-Caspase-3 activation and anti-apoptosis BCL-2/BCL-XL inhibition were found in primary hepatocytes treated with hydrogen peroxide(H2O2). TLR4 KO significantly inhibited CHOP and cleaved-Caspase-3 activation but activated BCL-2/BCL-XL. Functionally, both TLR4 KO and CHOP KO in hepatocytes resulted in reduced cell death induced by H2O2 treatment, as measured by LDH assay. In consistent with these in vitro findings, both TLR4 KO and CHOP KO protected livers against IR injury and hepatocellular cell death. Decreased protein levels of CHOP was found in livers post IR from TLR4 KO mice as compared to WT mice.
Conclusions: Our results indicated that TLR4-dependent CHOP activation mediated hepatocellular cell death during liver IR injury. Our findings provide a novel promising strategy for managing liver IR injury.
CITATION INFORMATION: Zhou H, Rao Z, Wang H, Wang X, Lu L. Toll-Like Receptor 4-Dependent CCAAT-Enhancer-Binding Protein Homologous Protein Activation Induces Hepatocellular Cell Death in Liver Ischemia and Reperfusion Injury. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Zhou H, Rao Z, Wang H, Wang X, Lu L. Toll-Like Receptor 4-Dependent CCAAT-Enhancer-Binding Protein Homologous Protein Activation Induces Hepatocellular Cell Death in Liver Ischemia and Reperfusion Injury. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/toll-like-receptor-4-dependent-ccaat-enhancer-binding-protein-homologous-protein-activation-induces-hepatocellular-cell-death-in-liver-ischemia-and-reperfusion-injury/. Accessed May 12, 2025.« Back to 2017 American Transplant Congress