Sensitivity of metallothionein-null mice to LPS/D-galactosamine-induced lethality.
Mice treated with lipopolysaccharide (LPS)/D-galactosamine (GalN) selectively develop hepatic failure. The acute-phase protein alpha(1)-acid glycoprotein (AGP) has been demonstrated to protect mice from LPS/GalN-induced lethality. Metallothionein (MT), which is a low-molecular weight, cysteine-rich, metal-binding protein, is also induced in the acute-phase reaction. However, the specific function of MT in acute-phase response remain to be elucidated. We showed that MT-null mice were more sensitive to LPS/GalN-induced lethality than wild-type mice. The increase in vital mediator levels, TNF-alpha and NO were of similar levels in wild-type and MT-null mice. A remarkable 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-type mice. These results indicated that MT may have the potential to prevent LPS/GalN-induced lethality, at least through the attenuation of AGP induction.
Kimura
T
T
Department of Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
Itoh
N
N
Takehara
M
M
Oguro
I
I
Ishizaki
J I
JI
Nakanishi
T
T
Tanaka
K
K
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D003643:Death; D004926:Escherichia coli; D005688:Galactosamine / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D008668:Metallothionein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009589:Nitrogen Oxides / Q000097:blood; D009961:Orosomucoid / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D008070:Lipopolysaccharides; D009589:Nitrogen Oxides; D009961:Orosomucoid; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D008668:Metallothionein