Abrogation of nuclear factor-kappaB activation is involved in zinc inhibition of lipopolysaccharide-induced tumor necrosis factor-alpha production and liver injury

Am J Pathol. 2004 May;164(5):1547-56. doi: 10.1016/s0002-9440(10)63713-3.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alanine Transaminase / metabolism
  • Animals
  • Endotoxins / metabolism
  • Enzyme Activation
  • I-kappa B Proteins / metabolism
  • Immunohistochemistry
  • Kupffer Cells / metabolism
  • Lipopolysaccharides / metabolism*
  • Liver / injuries*
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Oxidative Stress
  • Phosphorylation
  • Signal Transduction
  • Superoxides / metabolism
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism*
  • Zinc / metabolism*
  • Zinc / pharmacology


  • Endotoxins
  • I-kappa B Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • Nfkbia protein, mouse
  • Tumor Necrosis Factor-alpha
  • Superoxides
  • NF-KappaB Inhibitor alpha
  • Alanine Transaminase
  • Zinc