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

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• 作者：Ursula R. Sorg¹ ; ^&dagger ; ; Kristina Behnke¹ ; ² ; ^&dagger ; ; Daniel Degrandi¹ ; Maria Reich³ ; Verena Keitel³ ; Diran Herebian⁴ ; René ; Deenen⁵ ; Marc Beyer⁶ ; Joachim L. Schultze⁶ ; Karl K&ouml ; hrer⁵ ; Helmut E. Gabbert⁷ ; Ertan Mayatepek⁴ ; Dieter Hä ; ussinger³ ; Klaus Pfeffer¹ ; ^{Klaus.pfeffer@hhu.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：LTβR ; lymphotoxin β receptor ; TNFR ; tumor necrosis factor receptor ; WT ; wild-type ; PHx ; 70% partial hepatectomy ; BA ; bile acid ; GO ; gene ontology ; Mug ; murinoglobulin ; LW ; liver weight ; BW ; body weight ; AST ; aspartate transaminase ; ALT ; alanine transaminase ; ALP ; alkaline phosphatase ; T ; taurine ; G ; glycin
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：64
• 期：5
• 页码：1108-1117
• 全文大小：973 K

文摘

The liver exhibits a unique capacity for regeneration in response to injury. Lymphotoxin-β receptor (LTβR), 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 LTβR during pathophysiological alterations and its molecular mechanisms during liver regeneration are so far ill-characterized.

Methods

LTβR^−/− mice were subjected to 70% hepatectomy and liver regeneration capacity, bile acid profiles, and transcriptome analysis were performed.

Results

LTβR^−/− 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. LTβR and TNFRp55 share downstream signalling elements. Therefore, LTβR^−/− mice were treated with etanercept to create mice functionally deficient in both signalling pathways. Strikingly, the combined blockade of TNFRp55 and LTβR 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 LTβR^−/− and etanercept-treated LTβR^−/− vs. wild-type animals after PHx. Murinoglobulin 2 was identified as a significantly differentially regulated gene.

Conclusions

LTβR 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 LTβR signalling renders liver regeneration impossible.