title: Activation of the aryl hydrocarbon receptor sensitises human keratinocytes for CD95L- and TRAIL-induced apoptosis.
abstract: 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 β-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.
authors.affiliation: German Federal Institute for Risk Assessment, Department of Product Safety, Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Stolpmann
authors.forename: J
authors.initials: J
authors.lastname: Brinkmann
authors.forename: S
authors.initials: S
authors.lastname: Salzmann
authors.forename: D
authors.initials: D
authors.lastname: Genkinger
authors.forename: E
authors.initials: E
authors.lastname: Fritsche
authors.forename: C
authors.initials: C
authors.lastname: Hutzler
authors.forename: H
authors.initials: H
authors.lastname: Wajant
authors.forename: A
authors.initials: A
authors.lastname: Luch
authors.forename: F
authors.initials: F
authors.lastname: Henkler
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D018736:DNA Adducts / Q000737:chemistry; D053222:Fas Ligand Protein / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015398:Signal Transduction; D019324:beta-Naphthoflavone / Q000494:pharmacology
chemical_list: D018736:DNA Adducts; D053222:Fas Ligand Protein; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D001564:Benzo(a)pyrene; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D019324:beta-Naphthoflavone; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D053181:Caspase 8