Activation of the aryl hydrocarbon receptor sensitises human keratinocytes for CD95L- and TRAIL-induced apoptosis
| Autor: | Joep Brinkmann, Harald Wajant, Steffen Salzmann, Frank Henkler, Andreas Luch, Christoph Hutzler, Kristin Stolpmann, Doris Genkinger, E Fritsche |
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| Rok vydání: | 2012 |
| Předmět: |
Keratinocytes
Cancer Research Programmed cell death Fas Ligand Protein aryl hydrocarbon receptor (AhR) DNA damage HaCaT cells 7 8-Dihydro-7 8-dihydroxybenzo(a)pyrene 9 10-oxide Immunology Biology Caspase 8 Cell Line DNA Adducts Cellular and Molecular Neuroscience beta-Naphthoflavone Benzo(a)pyrene Cytochrome P-450 CYP1A1 Humans ddc:610 RNA Small Interfering apoptosis benzo[a]pyrene Cell Biology Aryl hydrocarbon receptor Fas receptor Cell biology Receptors TNF-Related Apoptosis-Inducing Ligand HaCaT human keratinocytes Receptors Aryl Hydrocarbon Biochemistry Apoptosis Cytochrome P-450 CYP1B1 CD95 biology.protein RNA Interference Original Article Aryl Hydrocarbon Hydroxylases Signal transduction Signal Transduction |
| Zdroj: | Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | In this study, we have analysed the apoptotic effects of the ubiquitous environmental toxin benzo[ a] pyrene (BP) in HaCaT cells and human keratinocytes. Although prolonged exposure to BP was not cytotoxic on its own, a strong enhancement of CD95 (Fas)-mediated apoptosis was observed with BP at concentrations activating the aryl hydrocarbon receptor (AhR). Importantly, the ultimately mutagenic BP-metabolite, that is, (+)-anti-BP-7,8-diol-9,10-epoxide (BPDE), failed to enhance CD95-mediated cell death, suggesting that the observed pro-apoptotic effect of BP is neither associated with DNA adducts nor DNA-damage related signalling. CD95-induced apoptosis was also enhanced by beta-naphtoflavone, a well-known agonist of the AhR that does not induce DNA damage, thus suggesting a crucial role for AhR activation. Consistently, BP failed to sensitise for CD95L-induced apoptosis in AhR knockdown HaCaT cells. Furthermore, inhibition of CYP1A1 and/or 1B1 expression did not affect the pro-apoptotic crosstalk. Exposure to BP did not increase expression of CD95, but led to augmented activation of caspase-8. Enhancement of apoptosis was also observed with the TRAIL death receptors that activate caspase-8 and apoptosis by similar mechanisms as CD95. Together, these observations indicate an interference of AhR signalling with the activity of receptor-associated signalling intermediates that are shared by CD95 and TRAIL receptors. Our data thus suggest that AhR agonists can enhance cytokine-mediated adversity upon dermal exposure. |
| Databáze: | OpenAIRE |
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