Cooperative role of lymphotoxin β receptor and tumor necrosis factor receptor p55 in murine liver regeneration

Background & Aims: The liver exhibits a unique capacity for regeneration in response to injury. Lymphotoxin-beta receptor (LT beta R), a core member of the tumor necrosis factor (TNF)/tumor necrosis factor receptor (TNFR) superfamily is known to play an important role in this process. However, the function of LT beta R during pathophysiological alterations and its molecular mechanisms during liver regeneration are so far ill-characterized. Methods: LT beta R-/- mice were subjected to 70% hepatectomy and liver regeneration capacity, bile acid profiles, and transcriptome analysis were performed. Results: LT beta R-/- deficient mice suffered from increased and prolonged liver tissue damage after 70% hepatectomy, accompanied by deregulated bile acid homeostasis. Pronounced differences in the expression patterns of genes relevant for bile acid synthesis and recirculation were observed. LT beta R and TNFRp55 share downstream signalling elements. Therefore, LT beta R-/- mice were treated with etanercept to create mice functionally deficient in both signalling pathways. Strikingly, the combined blockade of TNFRp55 and LT beta R signalling leads to complete failure of liver regeneration resulting in death within 24 to 48 h after PHx. Transcriptome analysis revealed a marked disparity in gene expression programs in livers of LT beta R-/- and etanercept-treated LT beta R-/- vs. wild-type animals after PHx. Murinoglobulin 2 was identified as a significantly differentially regulated gene. Conclusions: MR is essential for efficient liver regeneration and cooperates with TNFRp55 in this process. Differences in survival kinetics strongly suggest distinct functions for these two cytokine receptors in liver regeneration. Failure of TNFR and LT beta R signalling renders liver regeneration impossible. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.