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Activation of the aryl hydrocarbon receptor sensitises human keratinocytes for CD95L-and TRAIL-induced apoptosis
Please always quote using this URN: urn:nbn:de:bvb:20-opus-133501
- 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-apoptoticIn 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.…
Author: | K. Stolpmann, J. Brinkmann, S. Salzmann, D. Genkinger, E. Fritsche, C. Hutzler, H. Wajant, A. Luch, F. Henkler |
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URN: | urn:nbn:de:bvb:20-opus-133501 |
Document Type: | Journal article |
Faculties: | Medizinische Fakultät / Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II) |
Language: | English |
Parent Title (English): | Cell Death & Disease |
Year of Completion: | 2012 |
Volume: | 3 |
Issue: | e388 |
Source: | Cell Death and Disease (2012) 3, e388; doi:10.1038/cddis.2012.127 |
DOI: | https://doi.org/10.1038/cddis.2012.127 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | CD95; FAS; HaCaT cells; apoptosis; aryl hydrocarbon receptor (AhR); benzo[a]pyrene; cell death; dermatitis; growth-factor receptor; human keratinocytes; mediated apoptosis; mitochondrial dysfunction; pathways; progression; skin |
Release Date: | 2017/01/13 |
Licence (German): | CC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitung |