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- Title
Proinflammatory mesenchymal effects of the nongenotoxic hepatocarcinogen phenobarbital: a novel mechanism of antiapoptosis and tumor promotion.
- Authors
Riegler, Teresa; Nejabat, Marzieh; Eichner, Johannes; Stiebellehner, Melanie; Subosits, Sandra; Bilban, Martin; Zell, Andreas; Huber, Wolfgang W.; Schulte-Hermann, Rolf; Grasl-Kraupp, Bettina
- Abstract
Many environmental pollutants and drugs, including steroid hormones, hypolipidemics and antiepileptics, are nongenotoxic 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.
- Subjects
PHENOBARBITAL; CARCINOGENS; APOPTOSIS prevention; COCARCINOGENESIS; BIOLOGICAL crosstalk; EPITHELIAL cells; MESENCHYMAL stem cells; LIVER cells
- Publication
Carcinogenesis, 2015, Vol 36, Issue 12, p1521
- ISSN
0143-3334
- Publication type
Article
- DOI
10.1093/carcin/bgv135