Hepatocellular proliferation in response to a peroxisome proliferator doesnot require TNF alpha signaling

Rodents exposed to peroxisome proliferator xenobiotics respond with marked increases in hepatocellular replication and growth that results in tumor fo rmation. Recently, tumor necrosis factor-alpha (TNF alpha) was proposed as the central mediator of this maladaptive response. To define the role of TN F alpha signaling in hepatocellular growth induced by peroxisome proliferat ors we administered three daily gavage doses of the potent peroxisome proli ferator, 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 a nd hepatocyte proliferation. Lacking evidence that TNF alpha signaling medi ates these effects, we then examined the possible contribution of alternati ve cytokine pathways. Semi-quantitative, reverse transcriptase polymerase c hain reaction analysis revealed that wild type mice acutely exposed to Wy-1 4 643 had increased hepatic expression of Il1 beta, Il1r1, Hnf4, and Stat3 genes. Moreover, hepatic adenomas from mice chronically exposed to Wy-14 64 3 had increased expression of Il1 beta, Il1r1, Il6, and Ppary1. Expression of Il1 alpha, Tnf alpha, Tnfr1, Tnfr2, Ppar alpha, or C/ebp alpha was not a ltered by acute Wy-14 643 exposure or in adenomas induced by Wy-14643. Thes e data suggest that the hepatic mitogenesis and carcinogenesis associated w ith peroxisome proliferator exposure is not mediated via TNFa but instead m ay involve an alternative pathway requiring IL1 beta and IL6.