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(American Journal of Pathology. 2004;164:1547-1556.)
© 2004 American Society for Investigative Pathology

Abrogation of Nuclear Factor-B Activation Is Involved in Zinc Inhibition of Lipopolysaccharide-Induced Tumor Necrosis Factor- Production and Liver Injury

Zhanxiang Zhou^*, Lipeng Wang^*, Zhenyuan Song^*, Jack T. Saari, Craig J. McClain^* and Y. James Kang^*

From the Departments of Medicine^* and Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky; the Veterans Affairs Medical Center, Louisville, Kentucky; and the United States Department of Agriculture Grand Forks Human Nutrition Research Center, Grand Forks, North Dakota

Endotoxin (lipopolysaccharide, LPS)-induced tumor necrosis factor- (TNF-) release from Kupffer cells is critically involved in the pathogenesis of alcohol-induced liver injury. We recently reported that inhibition of alcohol-induced plasma endotoxin elevation contributes to the protective action of zinc against alcoholic hepatotoxicity. The present study was undertaken to determine whether zinc interferes with the endotoxin-TNF- signaling pathway, and possible mechanism(s) by which zinc modulates the endotoxin-TNF- signaling. Administration of LPS to metallothionein (MT)-knockout (MT-KO) mice and 129/Sv wild-type (WT) controls at 4 mg/kg induced hepatic TNF- elevation at 1.5 hours, followed by liver injury at 3 hours. Zinc pretreatment (two doses at 5 mg/kg) attenuated TNF- production and liver injury in both MT-KO and WT mice, indicating a MT-independent action of zinc. Immunohistochemical detection of the phosphorylation of I-B and nuclear factor (NF)-B in the liver of MT-KO mice demonstrated that zinc pretreatment abrogated LPS-induced NF-B activation in the Kupffer cells. Fluorescent microscopy of superoxide by dihydroethidine and of zinc ions by Zinquin in the liver of MT-KO mice showed that zinc pretreatment increased the intracellular labile zinc ions and inhibited LPS-induced superoxide generation. These results demonstrate that zinc inhibits LPS-induced hepatic TNF- production through abrogation of oxidative stress-sensitive NF-B pathway, and the action of zinc is independent of MT. Thus, zinc may be beneficial in the treatment of LPS-induced liver injuries, such as sepsis and alcoholism.

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