Role for tumor necrosis factor alpha receptor 1 and interleukin-1 receptorin the suppression of mouse hepatocyte apoptosis by the peroxisome proliferator nafenopin

Peroxisome proliferators (PPs) cause rodent liver enlargement and tumors. I n vitro, PPs induce rat and mouse hepatocyte DNA synthesis and suppress apo ptosis, a response mimicked by exogenous tumor necrosis factor a (TNF alpha ), Here, we determine the role of TNF receptor I (TNFR1), TNF receptor 2 (T NFR2), and nuclear factor kappa beta (NF kappa B) in the response of mouse hepatocytes to the PP, nafenopin. Nafenopin (50 mu mol/L) induced DNA synth esis as measured by bromodeoxyuridine (BrdU) incorporation, suppressed cell death as measured by Hoechst 33258 staining, induced peroxisomal beta-oxid ation as measured by cyanide insensitive palmitoyl CoA oxidation (PCO) and caused activation of nuclear factor kappa beta (NF kappa B) as determined b y electrophoretic mobility gel shift assay (EMSA). The induction of DNA syn thesis and the suppression of apoptosis in response to nafenopin was abroga ted completely by blocking antibodies to TNFR1 but not to TNFR2. In contras t, the induction of peroxisomal beta-oxidation by nafenopin was not blocked by the anti-TNFR1 antibody. Next, we evaluated the response of hepatocytes to interleukin-1 (IL-1), another proinflammatory cytokine, IL-1 alpha (2.5 ng/mL) and, to a lesser extent, IL-1 beta (5 ng/mL), shared the ability of TNF alpha to induce DNA synthesis and suppress apoptosis. In addition, ant i-IL-1 receptor, type Yp80 (IL-IR) antibodies were able to abrogate the res ponse to nafenopin, IL-1 alpha was still able to perturb hepatocyte growth in the presence of the anti-TNFR1 antibody suggesting that IL-1 alpha acts independently rather than by elaborating TNF alpha. In summary, these data provide additional evidence for a role for hepatic cytokines in the perturb ation of hepatocyte growth by PPs such as nafenopin.