Carcinogenesis, Vol. 22, No. 11, 1843-1851,
November 2001
© 2001 Oxford University Press
CARCINOGENESIS |
Hepatocellular proliferation in response to a peroxisome proliferator does not require TNF
signaling
CIIT Centers for Health Research, Research Triangle Park, NC 27709;
1 Graduate Program in Comparative Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA
Rodents exposed to peroxisome proliferator xenobiotics respond with marked increases in hepatocellular replication and growth that results in tumor formation. Recently, tumor necrosis factor-
(TNF) was proposed as the central mediator of this maladaptive response. To define the role of TNF signaling in hepatocellular growth induced by peroxisome proliferators we administered three daily gavage doses of the potent peroxisome proliferator, Wy-14 643, to mice nullizygous for TNF-receptor I (TNFR1), TNFR2, or both receptors. We demonstrate here that regardless of genotype the mice responded with almost identical increases in liver to body weight ratios and hepatocyte proliferation. Lacking evidence that TNF signaling mediates these effects, we then examined the possible contribution of alternative cytokine pathways. Semi-quantitative, reverse transcriptase polymerase chain reaction analysis revealed that wild type mice acutely exposed to Wy-14 643 had increased hepatic expression of Il1ß, Il1r1, Hnf4, and Stat3 genes. Moreover, hepatic adenomas from mice chronically exposed to Wy-14 643 had increased expression of Il1ß, Il1r1, Il6, and Ppar
1. Expression of Il1, Tnf, Tnfr1, Tnfr2, Ppar, or C/ebp was not altered by acute Wy-14 643 exposure or in adenomas induced by Wy-14643. These data suggest that the hepatic mitogenesis and carcinogenesis associated with peroxisome proliferator exposure is not mediated via TNF but instead may involve an alternative pathway requiring IL1ß and IL6.
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