Carcinogenesis, Vol 18, 2277-2280, Copyright © 1997 by Oxford University Press
M Rolfe, NH James and RA Roberts
Peroxisome proliferators (PPs) are a class of non-genotoxic rodent
hepatocarcinogens that cause increased hepatocyte DNA synthesis, peroxisome
proliferation and liver enlargement. We have demonstrated previously that
PPs suppress both spontaneous rat hepatocyte apoptosis and that induced by
the physiological negative regulator of liver growth, transforming growth
factor beta (TGF beta1). Evidence suggests that the suppression of
apoptosis by PPs is mediated via activation of the peroxisome proliferator
activated receptor-alpha (PPAR alpha), a member of the nuclear hormone
receptor superfamily. Here, we investigate the effects of tumour necrosis
factor alpha (TNF alpha) on cultured rat or mouse hepatocytes to determine
whether TNF alpha influences hepatocyte growth in a manner analogous to
that seen with PPs. Rat recombinant TNF alpha was found to stimulate DNA
synthesis and suppress apoptosis in isolated rat hepatocyte monolayers (P
< or = 0.01). These effects were seen in the range of 500-5000 U/ml with
a maximum effect at 5000 U/ml. Similarly, mouse recombinant TNF alpha was
able to stimulate DNA synthesis in mouse hepatocyte monolayers (P < or =
0.01) with a maximal effect at 1000 U/ml. Suppression of mouse hepatocyte
apoptosis by TNF alpha was not detected, possibly because of the low levels
of apoptosis under control conditions. However, when the levels of mouse
hepatocyte apoptosis were augmented using TGF beta1, TNF alpha caused a
significant suppression (P < or = 0.01). The neutralization of TNF alpha
using anti-TNF alpha antibodies abrogated significantly (P < or = 0.01)
the suppression of apoptosis by the PP, nafenopin. These data that suggest
TNF alpha may mediate, at least in part, the growth perturbation, liver
enlargement and hepatocarcinogenesis seen in response to the PP class of
non-genotoxic hepatocarcinogens.
ARTICLES
Tumour necrosis factor alpha (TNF alpha) suppresses apoptosis and induces DNA synthesis in rodent hepatocytes: a mediator of the hepatocarcinogenicity of peroxisome proliferators?
Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, UK.
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