title: Anti-apoptotic function of gelsolin in fas antibody-induced liver failure in vivo.
abstract: Apoptosis is a key mechanism underlying fulminant hepatic failure. The role of gelsolin in such apoptotic pathways is not well understood because both pro-apoptotic and anti-apoptotic effects have been reported in vitro, depending on the cell type and in vitro expression model used. Therefore, we studied an in vivo model of hepatic failure by analyzing expression of gelsolin; intrahepatic activation of caspase-3, -8, and -9; and the extent of apoptosis in gelsolin knockout (gsn(-/-)) versus wild-type mice (gsn(+/+)) after exposure to stimulatory Fas antibody Jo-2. Gelsolin was expressed exclusively in sinusoidal lining cells, including sinusoidal endothelial cells and Kupffer cells, of gsn(+/+) mice. Compared with wild-type mice, Jo2-exposed gsn(-/-) mice showed significantly higher numbers of apoptotic cells in the liver (22 +/- 9 versus 5 +/- 4% terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells, P = 0.002); shorter survival (P = 0.037); and enhanced activation of caspase-3 (P = 0.009), -8 (P = 0.004), and -9 (P = 0.004). Furthermore, inhibition of caspase-3 with z-DEVD-fmk blocked Jo2-induced liver failure in all mice. Thus, our data on Jo2-induced hepatic failure suggest that gelsolin exerts an overall anti-apoptotic effect in vivo. Moreover, selective expression of gelsolin in sinusoidal endothelial cells indicates a pivotal role for interactions between sinusoidal endothelial cells and liver parenchymal cells in Fas ligand-mediated liver failure.
authors.affiliation: Departments of Internal Medicine I, University of Bonn, Bonn, Germany. ludger.leifeld@ukb.uni-bonn.de
authors.forename: Ludger
authors.initials: L
authors.lastname: Leifeld
authors.forename: Klaus
authors.initials: K
authors.lastname: Fink
authors.forename: Grazyna
authors.initials: G
authors.lastname: Debska
authors.forename: Magdalene
authors.initials: M
authors.lastname: Fielenbach
authors.forename: Volker
authors.initials: V
authors.lastname: Schmitz
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
mesh_terms: D000818:Animals; D000906:Antibodies; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D018260:Gelsolin / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D017093:Liver Failure / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D019014:fas Receptor / Q000187:drug effects / Q000276:immunology
chemical_list: D000906:Antibodies; D018260:Gelsolin; D019014:fas Receptor; D020169:Caspases