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Toxic metals stimulate inflammatory cytokines in hepatocytes through oxidative stress mechanisms.

Authors
Dong-W; Simeonova-PP; Gallucci-R; Matheson-J; Flood-L; Wang-S; Hubbs-A; Luster-MI
Source
Toxicol Appl Pharmacol 1998 Aug; 151(2):359-366
NIOSHTIC No.
20025231
Abstract
Hepatocytes, as well as nonparenchymal cells, secrete proinflammatory cytokines and chemokines that are involved in the pathology of many liver diseases. In particular, tumor necrosis factor-alpha (TNFalpha), as well as members of the CXC family of chemokines, including interleukin (IL)-8 in humans and macrophage inflammatory protein (MIP)-2 in rodents, have been implicated in both damage and repair processes associated with various hepatotoxins. In the liver, cytokine secretion is usually associated with nonparenchymal cells, particularly Kupffer cells. In the present studies, cytokine gene expression and secretion were investigated in hepatocytes treated with cadmium chloride (CdCl2) or vanadium pentoxide (V2O5). Using human Hep G2 cells and freshly isolated rodent hepatocytes, it was demonstrated that metals increase gene expression and secretion of CXC chemokines and TNFalpha. IL-8 and MIP-2 secretion induced either by the metals or H2O2 were inhibited by antioxidants such as tetramethyl-thiourea and N-acetyl-cysteine. In vitro neutralization experiments with TNFalpha and in vivo studies with TNFalpha receptor knockout mice indicated that the metals directly stimulate CXC chemokine secretion without the need for TNFalpha. Taken together these studies indicate that, in addition to other inflammatory mediators and acute phase proteins, cytokines and chemokines are produced by hepatocytes, which may participate in hepatotoxic responses. The events responsible for their expression involve cellular redox changes.
Keywords
Metals; Hepatocytes; Vanadium-compounds; Cadmium-compounds; Liver-disorders; Liver-cancer; Tumors; In-vivo-studies; Antioxidants; In-vitro-studies
CODEN
TXAPA9
CAS No.
10108-64-2; 7440-43-9; 1314-62-1
Publication Date
19980801
Document Type
Journal Article
Fiscal Year
1998
NTIS Accession No.
NTIS Price
Issue of Publication
2
ISSN
0041-008X
NIOSH Division
HELD
Source Name
Toxicology and Applied Pharmacology
State
NC; WV
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