Role of cytokines in non-genotoxic hepatocarcinogenesis: cause or effect?

Chemicals with the potential to cause cancer through damaging DNA can be re adily identified in a range of in vitro screens that detect genotoxicity. H owever. many carcinogens are non-genotoxic yet cause rodent tumours, partic ularly in the liver. Some non-genotoxic carcinogens such as the peroxisome proliferators (PPs) act directly to cause liver growth and proliferation. w hereas others such as carbon tetrachloride cause liver damager followed by regenerative hyperplasia. Current data support a role for cytokines such as rumour necrosis factor alpha (TNF alpha) and interleukin (IL1) in hepatoca rcinogenesis. However, these data give rise to conflicting hypotheses: in s ome experimental models, TNF alpha appears to mediate damage, whereas in ot hers it is postulated to play a role in tissue repair. Recently, we have sh own that TNF alpha acting via TNF alpha receptor 1 and p38 MAP kinase suppr esses hepatocyte apoptosis. However, when new protein synthesis is disabled , TNF alpha becomes a death signal. An understanding of the role of cytokin es in rodent hepatocarcinogenesis will allow the development of markers tha t can be used to identify, at an early stage, those chemicals with the pote ntial to induce rodent tumours. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.