Abstract
Lymphotoxin-p-receptor deficient (LT beta R-/-) and Tumor Necrosis Factor Receptor p55 deficient (TNFRp55(-/-)) mice show defects in liver regeneration (LR) after partial hepatectomy (PHx) with significantly increased mortality. LT beta R and TNFRp55 belong to the core members of the TNF/TNFR superfamily. Interestingly, combined failure of LT beta R and TNFRp55 signaling after PHx leads to a ...
Abstract
Lymphotoxin-p-receptor deficient (LT beta R-/-) and Tumor Necrosis Factor Receptor p55 deficient (TNFRp55(-/-)) mice show defects in liver regeneration (LR) after partial hepatectomy (PHx) with significantly increased mortality. LT beta R and TNFRp55 belong to the core members of the TNF/TNFR superfamily. Interestingly, combined failure of LT beta R and TNFRp55 signaling after PHx leads to a complete defect in LR. Here, we first addressed the question which liver cell population crucially requires LT beta R signaling for efficient LR. To this end, mice with a conditionally targeted LT beta R allele (LT beta R-fl/fl) were crossed to AlbuminCre and Lysozy-meMCre mouse lines to unravel the function of the LT beta R on hepatocytes and monocytes/macrophages/Kupffer cells, respectively. Analysis of these mouse lines clearly reveals that LT beta R is required on hepatocytes for efficient LR while no deficit in LR was found in LT beta R-fl/fl x LysMCre mice. Second, the molecular basis for the cooperating role of LT beta R and TNFRp55 signaling pathways in LR was investigated by transcriptome analysis of etanercept treated LT beta R-/- (LT beta R-/-/ET) mice. Bioinformatic analysis and subsequent verification by qRT-PCR identified novel target genes (Cyclin-L2, Fas-Binding factor 1, interferon-related developmental regulator 1, Leucyl-tRNA Synthetase 2, and galectin-4) that are upregulated by LT beta R/TNFRp55 signaling after PHx and fail to be upregulated after PHx in LT beta R-/-/ET mice.
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