Alpha 1-acid glycoprotein and alpha 1-antitrypsin inhibit TNF-induced but not anti-Fas-induced apoptosis of hepatocytes in mice.
The acute phase proteins alpha 1-acid glycoprotein (alpha 1-AGP) and alpha 1-antitrypsin (alpha 1-AT) were shown to inhibit, by a mechanism unidentified to date, the lethality induced by TNF both in normal mice and in mice sensitized with galactosamine. We found that both bovine alpha 1-AGP and human alpha 1-AT also inhibited specifically the induction of apoptosis of hepatocytes by TNF/ galactosamine in vivo. This inhibition is specific for TNF, since apoptosis induced by TNF and actinomycin D was also inhibited, while similar apoptosis of hepatocytes induced by anti-Fas remained unaffected. The observation that these acute phase proteins did not affect the induction by TNF of IL-6, nitric oxide, or serum amyloid P excludes a nonselective inhibition of the TNF-activated pathways. The protection conferred by alpha 1-AGP and alpha 1-AT is presumably indirect, since these proteins did not inhibit TNF/actinomycin D-induced apoptosis in the hepatoma cell lines HepG2 and BWTG3.
Van Molle
W
W
Flanders Interuniversity Institute for Biotechnology, University of Ghent, Belgium.
Libert
C
C
Fiers
W
W
Brouckaert
P
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001667:Binding, Competitive / Q000276:immunology; D004247:DNA / Q000037:antagonists & inhibitors; D004338:Drug Combinations; D004587:Electrophoresis, Agar Gel; D005260:Female; D005688:Galactosamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D009961:Orosomucoid / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*; D019014:fas Receptor / Q000276:immunology*
D000911:Antibodies, Monoclonal; D004338:Drug Combinations; D009961:Orosomucoid; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D019014:fas Receptor; D005688:Galactosamine; D004247:DNA