Role of cytokines in non-genotoxic hepatocarcinogenesis: cause or effect?
Chemicals with the potential to cause cancer through damaging DNA can be readily identified in a range of in vitro screens that detect genotoxicity. However, many carcinogens are non-genotoxic yet cause rodent tumours, particularly in the liver. Some non-genotoxic carcinogens such as the peroxisome proliferators (PPs) act directly to cause liver growth and proliferation, whereas others such as carbon tetrachloride cause liver damage, followed by regenerative hyperplasia. Current data support a role for cytokines such as tumour necrosis factor alpha (TNFalpha) and interleukin 1 (IL1) in hepatocarcinogenesis. However, these data give rise to conflicting hypotheses; in some experimental models, TNFalpha appears to mediate damage, whereas in others it is postulated to play a role in tissue repair. Recently, we have shown that TNFalpha acting via TNFalpha receptor 1 and p38 MAP kinase suppresses hepatocyte apoptosis. However, when new protein synthesis is disabled, TNFalpha becomes a death signal. An understanding of the role of cytokines in rodent hepatocarcinogenesis will allow the development of markers that can be used to identify, at an early stage, those chemicals with the potential to induce rodent tumours.
Roberts
R A
RA
Syngenta Central Toxicology Laboratory, Alderley Park, Cheshire SK10 4TJ, Macclesfield, UK. ruth.roberts@syngenta.com
James
N H
NH
Cosulich
S
S
Hasmall
S C
SC
Orphanides
G
G
D016207:Cytokines / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D020025:Peroxisome Proliferators / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D020025:Peroxisome Proliferators; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases