title: Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-kappa B-independent, caspase-3-dependent pathway.
abstract: Agonistic antibodies against the Fas receptor, when administered to mice in vivo, cause significant apoptosis in the liver. In this study we show that anti-Fas antibody not only causes apoptosis of liver cells but also provokes hepatic inflammation. Two hours after injection of anti-Fas, when mice displayed evidence of caspase-3 activation and apoptosis, we found significant hepatic induction of the CXC chemokines macrophage inflammatory protein-2 and KC. Coincident with the chemokine induction was infiltration of the hepatic parenchyma by neutrophils. Neutralization experiments identified that chemokines were the cause of Fas-induced hepatic inflammation, with KC having the predominant effect. Chemokine induction in the livers of anti-Fas-treated mice was not associated with activation of NF-kappa B. Instead, it coincided with nuclear translocation of activator protein-1 (AP-1). AP-1 activation in liver was detected 1-2 h after anti-Fas treatment, suggesting a connection to the onset of apoptosis. When apoptosis was prevented by pretreating mice with a caspase-3 inhibitor, AP-1 activation and hepatic chemokine production were both significantly reduced. Hepatic inflammation was also reduced by 70%. Taken together, these findings indicate that Fas ligation can induce inflammation in the liver in vivo. Inflammation does not arise from Fas-mediated signaling through NF-kappa B; rather, it represents an indirect effect, requiring activation of caspase-3 and nuclear translocation of AP-1.
authors.affiliation: Liver Center and the Department of Medicine, University of California, San Francisco, California 94110, USA.
authors.forename: S
authors.initials: S
authors.lastname: Faouzi
authors.forename: B E
authors.initials: BE
authors.lastname: Burckhardt
authors.forename: J C
authors.initials: JC
authors.lastname: Hanson
authors.forename: C B
authors.initials: CB
authors.lastname: Campe
authors.forename: L W
authors.initials: LW
authors.lastname: Schrum
authors.forename: R A
authors.initials: RA
authors.lastname: Rippe
authors.forename: J J
authors.initials: JJ
authors.lastname: Maher
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000276:immunology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D002630:Chemotactic Factors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000378:metabolism; D006505:Hepatitis / Q000473:pathology / Q000503:physiopathology*; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D015846:Monokines / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration; D014020:Tissue Extracts / Q000737:chemistry; D018808:Transcription Factor AP-1 / Q000378:metabolism; D019014:fas Receptor / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061945:Caspase Inhibitors; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; D004791:Enzyme Inhibitors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D015846:Monokines; D016328:NF-kappa B; D014020:Tissue Extracts; D018808:Transcription Factor AP-1; D019014:fas Receptor; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases