High-level constitutive expression of alpha(1)-acid glycoprotein and lack of protection against tumor necrosis factor-induced lethal shock in transgenic mice

alpha(1)-Acid glycoprotein (AGP) is an acute phase protein produced by hepa tocytes. Although its exact biological function remains controversial, it w as shown to protect galactosamine-sensitized or normal mice against hepatit is and lethal shock induced by tumor necrosis factor (TNF). Rat-AGP-transge nic mice, constitutively producing several mg AGP per mi serum were tested for their response to a combined challenge with TNF and D-(+)-galactosamine , A previously characterized single transgenic line (9.5-5) was used. In co ntrast to our expectations both heterozygous or homozygous transgenic mice were not protected by the endogenously overproduced AGP. However, both tran sgenic and non-transgenic mice were protected by pretreatment with interleu kin-1, an effect which we believe is mediated by the induction of acute pha se proteins like AGP. Furthermore, both types of mice were protected by exo genous bovine AGP, suggesting that the lack of protection by endogenous AGP is not because of a repressed response to AGP. Finally, we demonstrate tha t purified AGP from the serum of transgenic mice is as protective as the AG P from non-transgenic mice or rats. The results suggest that AGP is protect ive only when its concentration is rapidly induced, perhaps because the end ogenous steady state synthesis of AGP, in non-transgenic as well as transge nic mice, is coupled to the production of an AGP-binding factor. This study provides an interesting example of differences in outcome to a lethal chal lenge between an acute administered and a chronically produced protective p rotein.