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Title: ABROGATION OF NUCLEAR FACTOR-KAPPA-B ACTIVATION IS INVOLVED IN ZINC INHIBITION OF LIPOPOLYSACCHARIDE-INDUCED TUMOR NECROSIS FACTOR-ALPHA PRODUCTION AND LIVER INJURY

Author
item ZHOU, ZHANXIANG - UNIV OF LOUISVILLE
item WANG, LIPENG - UNIV OF LOUISVILLE
item SONG, ZHENYUAN - UNIV OF LOUISVILLE
item Saari, Jack
item MCCLAIN, CRAIG - UNIV OF LOUISVILLE
item KANG, Y - UNIV OF LOUISVILLE

Submitted to: American Journal of Pathology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/5/2004
Publication Date: 5/1/2004
Citation: Zhou, Z., Wang, L., Song, Z., Saari, J.T., McClain, D.J., Kang, Y.J. 2004. Abrogation of nuclear factor-kappa-B activation is involved in zinc inhibition of lipopolysaccharide-induced tumor necrosis factor-alpha production and liver injury. American Journal of Pathology. 164(5):1547-1556.

Interpretive Summary: Excessive intake of alcohol causes liver damage by increasing production of toxic inflammatory molecules (endotoxins) by the gut. Prior studies in laboratory animals have shown that zinc can protect the liver against damage by alcohol, in part by inhibiting production of endotoxins. Although this protection has been associated with elevation of an antioxidant protein, metallothionein, a recent study showed that zinc could protect against alcoholic liver injury independently of metallothionein. The purpose of this study was to determine whether zinc, in addition to inhibiting production of endotoxins, also interferes with molecular signaling pathways caused by endotoxins and, secondarily, whether metallothionein was involved with this interference. Endotoxin treatment of mice caused elevation of a specific inflammatory molecule (TNF-alpha) known to be associated with alcoholic liver damage, as well as a molecule (NF-kappa-B) that mediates genetic expression of TNF-alpha. Zinc treatment inhibited production of both molecules, indicating that the signaling pathway leading to liver injury was suppressed and contributed to zinc's effectiveness. Further, this inhibition was independent of any change in metallothionein. This suggests that zinc treatment may have therapeutic potential for alcoholic liver damage.

Technical Abstract: Endotoxin (lipopolysaccharide, LPS)-induced tumor necrosis factor-alpha (TNF-alpha) 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 (1) whether zinc interferes with the endotoxin-TNF-alpha signaling pathway, and (2) possible mechanism(s) by which zinc modulates the endotoxin-TNF-alpha 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-alpha elevation at 1.5 hr, followed by liver injury at 3 h. Zinc pretreatment (2 doses at 5 mg/kg) attenuated TNF-alpha production and liver injury in both MT-KO and WT mice, indicating an MT-independent action of zinc. Immunohistochemical detection of the phosphorylation of I-kappa-B and NF-kappa-B in the liver of MT-KO mice demonstrated that zinc pretreatment abrogated LPS-induced NF-kappa-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-alpha production through abrogation of oxidative stress-sensitive NF-kappa-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.