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 α (TNFα), 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 β1-induced hepatocyte apoptosis (32% and 54% of control, respectively). Removal of non-parenchymal cells from normal hepatocyte cultures prevented both the nafenopin- and TNFα-induced increase in DNA synthesis and suppression of hepatocyte apoptosis; this response was restored by returning non-parenchymal cells to the purified hepatocytes. TNFα 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 TNFα released from non-parenchymal cells was small compared with that released spontaneously by hepatocytes. Nafenopin significantly increased the release of TNFα from non-parenchymal cells to 56 ± 18 pg/ml, but had little effect on TNFα release by hepatocytes. However, the concentration of exogenous TNFα 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 TNFα. However, the levels of TNFα released spontaneously or in response to peroxisome proliferators are insufficient per se to induce a growth response.
Keywords: EGF, epidermal growth factor receptor; NPC, non-parenchymal liver cell; PP, peroxisome proliferator; PPARα, peroxisome proliferator activated receptor α; TGFβ1, transforming growth factor β1; TNFα, tumour necrosis factor α.
Journal Article. 4746 words. Illustrated.
Subjects: Clinical Cytogenetics and Molecular Genetics
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