Sensitivity of metallothionein-null mice to LPS/D-galactosamine-induced lethality

Mice treated with lipopolysaccharide (LPS)/D-galactosamine (GalN) selective ly develop hepatic failure. The acute-phase protein alpha (1)-acid glycopro tein (AGP) has been demonstrated to protect mice from LPS/GalN-induced leth ality. Metallothionein (MT), which is a low-molecular weight, cysteine-rich , metal-binding protein, is also induced in the acute-phase reaction. Howev er, the specific function of MT in acute-phase response remain to be elucid ated. We showed that MT-null mice were more sensitive to LPS/GalN-induced l ethality than wild-type mice. The increase in vital mediator levels, TNF-al pha and NO were of similar levels in wild-type and MT-null mice. A remarkab le increase in plasma platelet activating factor levels was not observed in our experimental conditions. On the other hands, the mRNA level of AGP in the response to LPS/GalN was decreased in MT-null mice compared to wild-typ e mice. These results indicated that MT may have the potential to prevent L PS/GalN-induced lethality, at least through the attenuation of AGP inductio n. (C) 2001 Academic Press.