Abstract
Although it is well established that TNFα contributes to hepatitis, liver failure and associated hepatocarcinogenesis via the regulation of inflammation, its pro-apoptotic role in the liver has remained enigmatic. On its own, TNFα is unable to trigger apoptosis. However, when combined with the transcriptional inhibitor GaLN, it can cause hepatocyte apoptosis and liver failure in mice. Moreover, along with others, we have shown that TNFα is capable of sensitizing cells to FasL- or drug-induced cell death via c-Jun N-terminal kinase (JNK) activation and phosphorylation/activation of the BH3-only protein Bim. In this context, TNFα could exacerbate hepatocyte cell death during simultaneous inflammatory and T-cell-mediated immune responses in the liver. Here we show that TNFα sensitizes primary hepatocytes, established hepatocyte cell lines and mouse embryo fibroblasts to FasL-induced apoptosis by the transcriptional induction and higher surface expression of Fas via the NFκB pathway. Genetic deletion, diminished expression or dominant-negative inhibition of the NFκB subunit p65 resulted in lower Fas expression and inhibited TNFα-induced Fas upregulation and sensitization to FasL-induced cell death. By hydrodynamic injection of p65 shRNA into the tail vein of mice, we confirm that Fas upregulation by TNFα is also NFκB-mediated in the liver. In conclusion, TNFα sensitization of FasL-induced apoptosis in the liver proceeds via two parallel signaling pathways, activation of JNK and Bim phosphorylation and NFκB-mediated Fas upregulation.
Highlights
Introduction The death receptorFas (CD95/APO-1) plays a central role in maintaining liver homeostasis by contributing to the removal of senescent, virus infected and cancer cells
We could show by fluorescence-activated cell sorting (FACS) analysis using an anti-Fas antibody detecting the extracellular domain of Fas that two- to threefold more Fas was expressed on the surface of primary hepatocytes (Fig. 2d), Hepa[1,2,3,4,5,6] (Fig. 2e) and AML12 (Fig. 2f) cells after 14 h of TNFα treatment
We find that primary murine hepatocytes, as well as established hepatocyte and embryo fibroblast cell lines upregulate Fas in response to TNFα in an NFκBdependent manner
Summary
Introduction The death receptorFas (CD95/APO-1) plays a central role in maintaining liver homeostasis by contributing to the removal of senescent, virus infected and cancer cells. Engagement of Fas by its cognate ligand (FasL) triggers a caspase-8/-3-dependent signaling cascade resulting in apoptotic cell death. Mice injected with anti-Fas agonistic antibodies exhibit massive hepatocyte apoptosis and die of fulminant liver failure within a short time period[3,4]. Fas-mediated hepatocyte apoptosis is a common pathological feature of several human liver diseases[5,6,7,8,9,10,11]. Activation of tumor necrosis factor receptor 1 (TNFR1), unlike Fas, does not primarily lead to cell death in most cell types[12]. Upon binding of TNFα to TNFR1, complex 1 is assembled leading to nuclear factor 'kappa-light-chainenhancer' of activated B-cells (NFκB) activation, which induces a transcriptional program regulating inflammation, survival and proliferation. Under specific conditions, engagement of TNFR1 leads to the formation complex 2 or the necrosomal complex, which foster cell
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