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Activation of the aryl hydrocarbon receptor sensitises human keratinocytes for CD95L-and TRAIL-induced apoptosis

Zitieren Sie bitte immer diese 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.zeige mehrzeige weniger

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Metadaten
Autor(en): K. Stolpmann, J. Brinkmann, S. Salzmann, D. Genkinger, E. Fritsche, C. Hutzler, H. Wajant, A. Luch, F. Henkler
URN:urn:nbn:de:bvb:20-opus-133501
Dokumentart:Artikel / Aufsatz in einer Zeitschrift
Institute der Universität:Medizinische Fakultät / Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II)
Sprache der Veröffentlichung:Englisch
Titel des übergeordneten Werkes / der Zeitschrift (Englisch):Cell Death & Disease
Erscheinungsjahr:2012
Band / Jahrgang:3
Heft / Ausgabe:e388
Originalveröffentlichung / Quelle:Cell Death and Disease (2012) 3, e388; doi:10.1038/cddis.2012.127
DOI:https://doi.org/10.1038/cddis.2012.127
Allgemeine fachliche Zuordnung (DDC-Klassifikation):6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Freie Schlagwort(e):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
Datum der Freischaltung:13.01.2017
Lizenz (Deutsch):License LogoCC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitung