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  - 
TY  - JOUR
A1  - Panayotova-Dimitrova, Diana
A1  - Feoktistova, Maria
A1  - Ploesser, Michaela
A1  - Kellert, Beate
A1  - Hupe, Mike
A1  - Horn, Sebastian
A1  - Makarov, Roman
A1  - Jensen, Federico
A1  - Porubsky, Stefan
A1  - Schmieder, Astrid
A1  - Zenclussen, Ana Claudia
A1  - Marx, Alexander
A1  - Kerstan, Andreas
A1  - Geserick, Peter
A1  - He, You-Wen
A1  - Leverkus, Martin
T1  - cFLIP Regulates Skin Homeostasis and Protects against TNF-Induced Keratinocyte Apoptosis
JF  - Cell Reports
N2  - FADD, caspase-8, and cFLIP regulate the outcome of cell death signaling. Mice that constitutively lack these molecules die at an early embryonic age, whereas tissue-specific constitutive deletion of FADD or caspase-8 results in inflammatory skin disease caused by increased necroptosis. The function of cFLIP in the skin in vivo is unknown. In contrast to tissue-specific caspase-8 knockout, we show that mice constitutively lacking cFLIP in the epidermis die around embryonic days 10 and 11. When cFLIP expression was abrogated in adult skin of cFLIP(fl/fl)-K14CreER(tam) mice, severe inflammation of the skin with concomitant caspase activation and apoptotic, but not necroptotic, cell death developed. Apoptosis was dependent of autocrine tumor necrosis factor production triggered by loss of cFLIP. In addition, epidermal cFLIP protein was lost in patients with severe drug reactions associated with epidermal apoptosis. Our data demonstrate the importance of cFLIP for the integrity of the epidermis and for silencing of spontaneous skin inflammation.
KW  - eczematous dermatitis
KW  - programmed necrosis
KW  - gene induction
KW  - in-vivo
KW  - activation
KW  - mediated apoptosis
KW  - c-flip
KW  - cell-death
KW  - Stevens-Johnson syndrome
KW  - toxic epidermal necrolysis
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122155
VL  - 5
ER  -