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 mechan ism unidentified to date, the lethality induced by TNF both in normal mice and in mice sensitized with galactosamine. We found that both bov ine alpha(1)-AGP and human alpha(1)-AT also inhibited specifically the induction of apoptosis of hepatocytes by TNF/galactosamine in vivo. T his inhibition is specific for TNF, since apoptosis induced by TNF and actinomycin D was also inhibited, while similar apoptosis of hepatocy tes induced by anti-Fas remained unaffected. The observation that thes e acute phase proteins did not affect the induction by TNF of IL-6, ni tric oxide, or serum amyloid P excludes a nonselective inhibition of t he TNF-activated pathways. The protection conferred by alpha(1)-AGP an d alpha(1)-AT is presumably indirect, since these proteins did not inh ibit TNF/actinomycin D-induced apoptosis in the hepatoma cell lines He pG2 and BWTG3.