Tumour necrosis factor α (TNFα) suppresses apoptosis and induces DNA synthesis in rodent hepatocytes: A mediator of the hepatocarcinogenicity of peroxisome proliferators?

Abstract

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 β (TGFβ1). Evidence suggests that the suppression of apoptosis by PPs is mediated via activation of the peroxisome proliferator activated receptor-α (PPARα), a member of the nuclear hormone receptor superfamily. Here, we investigate the effects of tumour necrosis factor α (TNFα) on cultured rat or mouse hepatocytes to determine whether TNFα influences hepatocyte growth in a manner analogous to that seen with PPs. Rat recombinant TNFα was found to stimulate DNA synthesis and suppress apoptosis in isolated rat hepatocyte monolayers (P ≤ 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 TNFα was able to stimulate DNA synthesis in mouse hepatocyte monolayers (P ≤ 0.01) with a maximal effect at 1000 U/ml. Suppression of mouse hepatocyte apoptosis by TNFα 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 TGFβ1, TNFα caused a significant suppression (P ≤ 0.01). The neutralization of TNFα using anti-TNFα antibodies abrogated significantly (P ≤ 0.01) the suppression of apoptosis by the PP, nafenopin. These data that suggest TNFα may mediate, at least in part, the growth perturbation, liver enlargement and hepatocarcinogenesis seen in response to the PP class of non-genotoxic hepatocarcinogens.