F. Kayama et al., ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA IN CADMIUM-INDUCED HEPATOTOXICITY, Toxicology and applied pharmacology, 131(2), 1995, pp. 224-234
Liver and kidney injury following acute or chronic exposure to cadmium
is well characterized. While hepatocytes and endothelial cells of the
sinusoids are thought to be the primary cellular targets in the liver
, ultrastructural changes may vary depending upon the exposure regimen
and the time following administration. Since acute and chronic liver
disease is often associated with the presence of cytokines, we investi
gated the role of proinflammatory cytokines in cadmium-induced hepatot
oxicity. Supernatants from cultured liver slices obtained from acute o
r subchronic cadmium-exposed rats and mice were collected and cytokine
secretion was examined. In addition, mRNA transcripts for IL-1 alpha,
IL-1 beta, IL-6, TNF-alpha, MIP-2, IFN-gamma, and ICAM-1 from livers
of treated mice were quantitated by reverse transcription-polymerase c
hain reaction. Modest increases in secretion of TNF-alpha, IL-1 alpha,
and IL-6 were observed in response to cadmium which were enhanced in
LPS-primed mice. Additionally, cadmium exposure increased IL-1 alpha,
IL-1 beta, TNF-alpha, MIP-2, IL-6, and ICAM-1 mRNA transcripts in the
liver. Immunohistochemical analysis revealed that TNF-alpha was associ
ated with nonparenchymal cells in livers of cadmium-treated mice. Cadm
ium exposure produced a marked increase in plasma hepatocellular enzym
e levels (i.e., AST, LDH, SDH), acute phase proteins (i.e., serum amyl
oid A), and foci formation in the liver, while focal inflammation and
serum amyloid A (SAA) secretion, but not plasma enzymes, were further
increased in cadmium-exposed mice primed with LPS. SAA secretion and f
ocal inflammation were prevented by pretreatment with antibodies to TN
F-alpha, indicating that these pathological manifestations are cytokin
e dependent. These data indicate that TNF-alpha, released from nonpare
nchymal cells as well as associated cytokines, are responsible for cer
tain manifestations observed with cadmium-induced hepatotoxicity.