Carcinogenesis, Vol. 21, No. 12, 2159-2165,
December 2000
© 2000 Oxford University Press
CANCER BIOLOGY |
Role of hepatic non-parenchymal cells in the response of rat hepatocytes to the peroxisome proliferator nafenopin in vitro
Cancer Biology Group, Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK
Induction of liver cancer by peroxisome proliferators such as nafenopin is frequently associated with increased liver growth, increased DNA synthesis and suppression of apoptosis. The cytokine, tumour necrosis factor 
(TNF), and non-parenchymal liver cells have been implicated in mediating the hepatic response to peroxisome proliferators. Here, we have investigated the dependency of the hepatocyte response to peroxisome proliferators on non-parenchymal cells, a major source of hepatic cytokines. Addition of non-parenchymal cells, or conditioned medium from non-parenchymal cell cultures, increased DNA synthesis (220% and 270% of control, respectively) and suppressed transforming growth factor ß1-induced hepatocyte apoptosis (32% and 54% of control, respectively). Removal of non-parenchymal cells from normal hepatocyte cultures prevented both the nafenopin- and TNF-induced increase in DNA synthesis and suppression of hepatocyte apoptosis; this response was restored by returning non-parenchymal cells to the purified hepatocytes. TNF was detected in the medium of non-parenchymal cell (3–15 pg/ml) and normal hepatocyte cultures (25–100 pg/ml) by bioassay using L929 cells. However, the contribution of TNF released from non-parenchymal cells was small compared with that released spontaneously by hepatocytes. Nafenopin significantly increased the release of TNF from non-parenchymal cells to 56 ± 18 pg/ml, but had little effect on TNF release by hepatocytes. However, the concentration of exogenous TNF required to elicit a response in hepatocytes was 100 pg/ml and above. These data provide evidence that hepatic non-parenchymal cells are permissive for the growth response of hepatocytes in vitro to peroxisome proliferators and this may be mediated, at least in part by TNF. However, the levels of TNF released spontaneously or in response to peroxisome proliferators are insufficient per se to induce a growth response.
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