Sensitivity of Metallothionein-Null Mice to LPS/-Galactosamine-Induced Lethality

Itoh

Takehara

et al. 2003

Self Cite

Zinc is an essential and multifunctional element for all cells. Metallothionein (MT) is a low molecular weight, cystein-rich, metal-binding protein that is involved in zinc homeostasis. During the acute-phase reaction, hepatic MT production is induced and hepatic zinc accumulation is stimulated. We previously reported that MT-I and IIdeficient (MT-null) mice are highly sensitive to the lethal effects of lipopolysaccharide (LPS) plus D-galactosamine (GalN). The sensitization may relate to attenuatoin of α 1 -acid glycoprotein (AGP) expression in MT-null mice. In the present study, we hypothesized that MT-induced hepatic zinc accumulation promotes AGP expression and prevents LPS/GalN-induced lethality. To determine whether zinc reduces LPS/GalN toxicity, zinc was administered to mice. Simultaneous administration of zinc and LPS/GalN showed no effect on the lethality of LPS/GalN in mice. Zinc administration at 3 hr prior to LPS/GalN challenge reduced LPS/GalN-induced death. However, zinc pre-administration at 24 hr before LPS/GalN challenge did not reduce LPS/GalN-induced death. The expression of AGP mRNA was elevated at 3 hr after zinc administration, 24-hr pretreatment was ineffective. The protective effect of zinc was observed in both wild-type and MT-null mice. These results show that the protective effects of zinc were not caused by MT induction, but by AGP expression. We suggest that MT-induced hepatic zinc accumulation may promote AGP expression and thus prevent LPS/GalN-induced lethality.

Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 92%

See 1 more Smart Citation

Protective Effect of Zinc against Lipopolysaccharide/D-Galactosamine-Induced Lethality.

Itoh

Takehara

et al. 2003

Self Cite

“…It is known that MT-KO mice are hypersensitive to lipopolysaccharide (LPS)-induced coagulatory disturbance 23) and LPS/D-galactosamine-induced lethality. 24,25) It is possible that this hypersensitivity is related to a lack of MT-mediated MTF-1 activation.…”

Section: Resultsmentioning

confidence: 99%

Metal Response Element-binding Transcription Factor-1 Is Activated by Degradation of Metallothionein

Okumura

Oguro

et al. 2009

Self Cite

Cytosolic zinc-binding protein, metallothionein (MT), is normally saturated with Zn. It is thought that Znsaturated MT (Zn-MT) acts as a major intracellular Zn pool. Metal-response element-binding transcription factor-1 (MTF-1) plays an important role in Zn-mediated MT transcription. Here, we showed that degradation of Zn-MT activates MTF-1. We measured activated MTF-1 using an electrophoretic mobility shift assay. Interleukin-6 induced MT expression and increased MTF-1 activity. MTF-1 activation was not observed in MT-overexpressing cells. MT-dependent MTF-1 activation was observed only after treating MT-overexpressing cells with cycloheximide (CHX), a protein synthesis inhibitor. CHX-treatment increased the degradation/synthesis ratio of protein. An increase in the degradation/synthesis ratio for the MT protein is expected to increase the level of labile Zn and activate MTF-1. Recombinant MTF-1 was activated by H 2 O 2 only in the presence of Zn-MT. Oxidative stress activated MTF-1 DNA-binding activity in primary cultured hepatocytes but not in MT-deficient hepatocytes. These findings suggest that degradation of Zn-MT activates MTF-1, and that MT plays an important role in zinc-mediated signal transduction.

“…12) However, the major cause of the differences in the sensitivity to the lethal effects of LPS/GalN between wild type and MT-null mice remained unknown. Here, we found that historical grade of hepatocellular necrosis was greater in MT-null mice than in wild type mice.…”

Section: Resultsmentioning

confidence: 99%

Metallothionein-Null Mice Are Sensitive to Endotoxine/D-Galactosamine-Induced Hepatotoxicity.

Koujitani

Itoh

et al. 2001

Self Cite

Metallothionein (MT), which is a low-molecular weight, cysteine-rich, metal-binding protein, is induced during acute-phase reactions. However, the specific function of MT in the acute-phase response remains to be elucidated. We previously reported that MT-I, II deficient (MT-null) mice are highly sensitive to the lethal effects of lipopolysaccharide (LPS)/D-galactosamine (GalN). We designed the present study to clarify the major cause of the differences in the sensitivity to the lethal effects of LPS/GalN between wild type and MT-null mice. We found that histological grade of hepatocellular necrosis, induced by LPS/GalN, was greater in MT-null mice than in wild type mice. Therefore, the present findings suggest that MT induction has the potential as an attenuator of LPS/GalNinduced liver necrosis.