title: Role for tumor necrosis factor alpha receptor 1 and interleukin-1 receptor in the suppression of mouse hepatocyte apoptosis by the peroxisome proliferator nafenopin.
abstract: Peroxisome proliferators (PPs) cause rodent liver enlargement and tumors. In vitro, PPs induce rat and mouse hepatocyte DNA synthesis and suppress apoptosis, a response mimicked by exogenous tumor necrosis factor alpha (TNFalpha). Here, we determine the role of TNF receptor 1 (TNFR1), TNF receptor 2 (TNFR2), and nuclear factor kappa beta (NFkappaB) in the response of mouse hepatocytes to the PP, nafenopin. Nafenopin (50 micromol/L) induced DNA synthesis as measured by bromodeoxyuridine (BrdU) incorporation, suppressed cell death as measured by Hoechst 33258 staining, induced peroxisomal beta-oxidation as measured by cyanide insensitive palmitoyl CoA oxidation (PCO) and caused activation of nuclear factor kappa beta (NFkappaB) as determined by electrophoretic mobility gel shift assay (EMSA). The induction of DNA synthesis and the suppression of apoptosis in response to nafenopin was abrogated completely by blocking antibodies to TNFR1 but not to TNFR2. In contrast, 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-1alpha (2.5 ng/mL) and, to a lesser extent, IL-1beta (5 ng/mL), shared the ability of TNFalpha to induce DNA synthesis and suppress apoptosis. In addition, anti-IL-1 receptor, type 1/p80 (IL-1R) antibodies were able to abrogate the response to nafenopin. IL-1alpha was still able to perturb hepatocyte growth in the presence of the anti-TNFR1 antibody suggesting that IL-1alpha acts independently rather than by elaborating TNFalpha. In summary, these data provide additional evidence for a role for hepatic cytokines in the perturbation of hepatocyte growth by PPs such as nafenopin.
authors.affiliation: Cancer Biology Group, AstraZeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: West
authors.forename: N H
authors.initials: NH
authors.lastname: James
authors.forename: S C
authors.initials: SC
authors.lastname: Cosulich
authors.forename: P R
authors.initials: PR
authors.lastname: Holden
authors.forename: R
authors.initials: R
authors.lastname: Brindle
authors.forename: M
authors.initials: M
authors.lastname: Rolfe
authors.forename: R A
authors.initials: RA
authors.lastname: Roberts
mesh_terms: D000818:Animals; D000906:Antibodies; D015703:Antigens, CD / Q000737:chemistry / Q000145:classification / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008099:Liver / Q000166:cytology* / Q000187:drug effects; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009255:Nafenopin / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D020025:Peroxisome Proliferators / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020675:Peroxisomes / Q000187:drug effects / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000145:classification / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D016196:S Phase / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D007375:Interleukin-1; D016328:NF-kappa B; D020025:Peroxisome Proliferators; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D009255:Nafenopin; D004247:DNA