title: Proinflammatory mesenchymal effects of the non-genotoxic hepatocarcinogen phenobarbital: a novel mechanism of antiapoptosis and tumor promotion.
abstract: Many environmental pollutants and drugs, including steroid hormones, hypolipidemics and antiepileptics, are non-genotoxic carcinogens (NGC) in rodent liver. The mechanism of action and the risk for human health are still insufficiently known. Here, we study the effects of phenobarbital (PB), a widely used model NGC, on hepatic epithelial-mesenchymal crosstalk and the impact on hepatic apoptosis. Mesenchymal cells (MC) and hepatocytes (HC) were isolated from control and PB-treated rat livers. PB induced extensive changes in gene expression in MC and much less in HC as shown by transcriptomics with oligoarrays. In MC only, transcript levels of numerous proinflammatory cytokines were elevated. Correspondingly, ELISA on the supernatant of MC from PB-treated rats revealed enhanced release of various cytokines. In cultured HC, this supernatant caused (i) nuclear translocation and activation of nuclear factor-κB (shown by immunoblots of nuclear extracts and reporter gene assays), (ii) elevated expression of proinflammatory genes and (iii) protection from the proapoptotic action of transforming growth factor beta 1 (TGFß1). PB treatment in vivo or in vitro elevated the production and release of tumor necrosis factor alpha from MC, which was identified as mainly responsible for the inhibition of apoptosis in HC. In conclusion, our findings reveal profound proinflammatory effects of PB on hepatic mesenchyme and mesenchymal-epithelial interactions. The resulting release of cytokines acts antiapoptotic in HC, an effect crucial for tumor promotion and carcinogenesis by NGC.
authors.forename: Teresa
authors.initials: T
authors.lastname: Riegler
authors.forename: Marzieh
authors.initials: M
authors.lastname: Nejabat
authors.affiliation: Center of Bioinformatics Tübingen (ZBIT), University of Tübingen, 72070 Tübingen, Germany and.
authors.forename: Johannes
authors.initials: J
authors.lastname: Eichner
authors.forename: Melanie
authors.initials: M
authors.lastname: Stiebellehner
authors.forename: Sandra
authors.initials: S
authors.lastname: Subosits
authors.affiliation: Department of Laboratory Medicine and Core Facility Genomics, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.affiliation: Center of Bioinformatics Tübingen (ZBIT), University of Tübingen, 72070 Tübingen, Germany and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zell
authors.forename: Wolfgang W
authors.initials: WW
authors.lastname: Huber
authors.forename: Rolf
authors.initials: R
authors.lastname: Schulte-Hermann
authors.forename: Bettina
authors.initials: B
authors.lastname: Grasl-Kraupp
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D010634:Phenobarbital / Q000633:toxicity*; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D002273:Carcinogens; D016328:NF-kappa B; D018009:Receptors, Glycine; D010634:Phenobarbital