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

Zhanxiang Zhou, Lipeng Wang, Zhenyuan Song, Jack T. Saari, Craig J. McClain, Yujian Kang

Research output: Contribution to journalArticle

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Abstract

Endotoxin (lipopolysaccharide, LPS)-induced tumor necrosis factor-α (TNF-α) 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-α signaling pathway, and possible mechanism(s) by which zinc modulates the endotoxin-TNF-α 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-α elevation at 1.5 hours, followed by liver injury at 3 hours. Zinc pretreatment (two doses at 5 mg/kg) attenuated TNF-α 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-κB and nuclear factor (NF)-κB in the liver of MT-KO mice demonstrated that zinc pretreatment abrogated LPS-induced NF-κB 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-α production through abrogation of oxidative stress-sensitive NF-κB 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.

Original languageEnglish (US)
Pages (from-to)1547-1556
Number of pages10
JournalAmerican Journal of Pathology
Volume164
Issue number5
DOIs
StatePublished - Jan 1 2004
Externally publishedYes

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Lipopolysaccharides
Zinc
Tumor Necrosis Factor-alpha
Metallothionein
Liver
Wounds and Injuries
Endotoxins
Kupffer Cells
Superoxides
Alcohols
Ions
Knockout Mice
Alcoholism
Microscopy
Sepsis
Oxidative Stress
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Abrogation of Nuclear Factor-κB Activation Is Involved in Zinc Inhibition of Lipopolysaccharide-Induced Tumor Necrosis Factor-α Production and Liver Injury. / Zhou, Zhanxiang; Wang, Lipeng; Song, Zhenyuan; Saari, Jack T.; McClain, Craig J.; Kang, Yujian.

In: American Journal of Pathology, Vol. 164, No. 5, 01.01.2004, p. 1547-1556.

Research output: Contribution to journalArticle

Zhou, Zhanxiang ; Wang, Lipeng ; Song, Zhenyuan ; Saari, Jack T. ; McClain, Craig J. ; Kang, Yujian. / Abrogation of Nuclear Factor-κB Activation Is Involved in Zinc Inhibition of Lipopolysaccharide-Induced Tumor Necrosis Factor-α Production and Liver Injury. In: American Journal of Pathology. 2004 ; Vol. 164, No. 5. pp. 1547-1556.
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