TY  - JOUR
A1  - Stolpmann, K.
A1  - Brinkmann, J.
A1  - Salzmann, S.
A1  - Genkinger, D.
A1  - Fritsche, E.
A1  - Hutzler, C.
A1  - Wajant, H.
A1  - Luch, A.
A1  - Henkler, F.
T1  - Activation of the aryl hydrocarbon receptor sensitises human keratinocytes for CD95L-and TRAIL-induced apoptosis
JF  - Cell Death & Disease
N2  - 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.
KW  - CD95
KW  - HaCaT cells
KW  - growth-factor receptor
KW  - cell death
KW  - mitochondrial dysfunction
KW  - mediated apoptosis
KW  - FAS
KW  - dermatitis
KW  - pathways
KW  - skin
KW  - progression
KW  - aryl hydrocarbon receptor (AhR)
KW  - apoptosis
KW  - benzo[a]pyrene
KW  - human keratinocytes
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133501
VL  - 3
IS  - e388
ER  -