| First Author | Zhou Z | Year | 2004 |
| Journal | Am J Pathol | Volume | 164 |
| Issue | 5 | Pages | 1547-56 |
| PubMed ID | 15111301 | Mgi Jnum | J:89568 |
| Mgi Id | MGI:3040742 | Doi | 10.1016/s0002-9440(10)63713-3 |
| Citation | Zhou Z, et al. (2004) 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 164(5):1547-56 |
| abstractText | 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. |
