Abrogation of nuclear factor-kappaB activation is involved in zinc inhibition of lipopolysaccharide-induced tumor necrosis factor-alpha production and liver injury.
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 whether zinc interferes with the endotoxin-TNF-alpha signaling pathway, and 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 hours, followed by liver injury at 3 hours. Zinc pretreatment (two doses at 5 mg/kg) attenuated TNF-alpha 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-kappaB and nuclear factor (NF)-kappaB in the liver of MT-KO mice demonstrated that zinc pretreatment abrogated LPS-induced NF-kappaB 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-kappaB 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.
Zhou
Zhanxiang
Z
Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA. z0zhou01@louisville.edu
Wang
Lipeng
L
Song
Zhenyuan
Z
Saari
Jack T
JT
McClain
Craig J
CJ
Kang
Y James
YJ
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D004731:Endotoxins / Q000378:metabolism; D004789:Enzyme Activation; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D007728:Kupffer Cells / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D008099:Liver / Q000293:injuries* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
D004731:Endotoxins; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D000072000:NF-KappaB Inhibitor alpha; D000410:Alanine Transaminase; D015032:Zinc