Tumour necrosis factor alpha (TNF alpha) suppresses apoptosis and induces DNA synthesis in rodent hepatocytes: a mediator of the hepatocarcinogenicity of peroxisome proliferators?
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.