Abstract
There is increasing evidence that active contribution of the hepatocyte to liver disease is strongly dependent on the local cytokine environment. Most recently, it has been shown in vitro that tumor necrosis factor alpha (TNFα) can enhance hepatocyte FasL-mediated cytotoxicity. The present in vivo study examined the relevance of the Fas/FasL pathway for hepatocellular apoptosis in a TNFα-driven model of acute liver failure. Fas wild type (wt) and Fas lpr (lymphoproliferation) mutant mice Fas (lpr/lpr) pretreated with either soluble TNFα-receptor or saline were exposed to galactosamine (Gal) and E. coli lipopolysaccharide (LPS). In Fas wt mice, Gal/LPS-exposed livers highly expressed not only Fas but also FasL and revealed marked tissue damage with hepatocellular apoptosis (in vivo microscopy: 268 ± 20 cells/mm2), cleavage of caspase-3 protein, sinusoidal perfusion failure and alanine aminotransferase (ALT) release (497 ± 106 U/L) which was almost completely prevented by application of the soluble TNFα-receptor (apoptotic hepatocytes/mm2: 19 ± 4; ALT: 103 ± 19 U/L). Fas lpr/lpr mice revealed markedly lower FasL upregulation and were significantly protected against Gal/LPS-induced apoptosis (apoptotic hepatocytes/mm2: 65 ± 4) and necrosis (ALT: 252 ± 73 U/L). Additional neutralization of TNFα could further reduce apoptotic cell death (apoptotic hepatocytes/mm2: 36 ± 9). Two colour flow cytometry revealed that TNFα-induced apoptosis of HepG2 cells which was associated with both Fas and FasL upregulation could significantly be prevented by addition of a FasL-neutralizing antibody.
Taken together, our data provide evidence for a direct link between TNFα and Fas/FasL in mediating hepatocyte apoptosis upon Gal/LPS exposure. The TNFα-induced hepatocellular upregulation of Fas and FasL allows their apoptosis by this ligand-receptor interaction. Thus, hepatocytes must be considered as active contributors in Gal/LPS-induced liver injury.
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© 2008 Springer Medizin Verlag Heidelberg
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Kuhla, A., Eipel, C., Abshagen, K., Menger, M.D., Ibrahim, S., Vollmar, B. (2008). Bedeutung der TNFα-abhängigen Fas/FasL-Zytotoxizität für die hepatozelluläre Apoptose im Modell des Gal/LPS-induzierten akuten Leberversagens. In: Arbogast, R., Schackert, H.K., Bauer, H. (eds) Chirurgisches Forum 2008. Deutsche Gesellschaft für Chirurgie, vol 37. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-78833-1_4
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DOI: https://doi.org/10.1007/978-3-540-78833-1_4
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-78821-8
Online ISBN: 978-3-540-78833-1
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