Description:
<jats:title>Abstract</jats:title>
<jats:p>Lymphotoxin-β-receptor deficient (LTβR<jats:sup>−/−</jats:sup>) and Tumor Necrosis Factor Receptor p55 deficient (TNFRp55<jats:sup>−/−</jats:sup>) mice show defects in liver regeneration (LR) after partial hepatectomy (PHx) with significantly increased mortality. LTβR and TNFRp55 belong to the core members of the TNF/TNFR superfamily. Interestingly, combined failure of LTβR and TNFRp55 signaling after PHx leads to a complete defect in LR. Here, we first addressed the question which liver cell population crucially requires LTβR signaling for efficient LR. To this end, mice with a conditionally targeted LTβR allele (LTβR<jats:sup>fl/fl</jats:sup>) were crossed to AlbuminCre and LysozymeMCre mouse lines to unravel the function of the LTβR on hepatocytes and monocytes/macrophages/Kupffer cells, respectively. Analysis of these mouse lines clearly reveals that LTβR is required on hepatocytes for efficient LR while no deficit in LR was found in LTβR<jats:sup>fl/fl</jats:sup> × LysMCre mice. Second, the molecular basis for the cooperating role of LTβR and TNFRp55 signaling pathways in LR was investigated by transcriptome analysis of etanercept treated LTβR<jats:sup>−/−</jats:sup> (LTβR<jats:sup>−/−</jats:sup>/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 LTβR/TNFRp55 signaling after PHx and fail to be upregulated after PHx in LTβR<jats:sup>−/−</jats:sup>/ET mice.</jats:p>