title: The contact allergen nickel sensitizes primary human endothelial cells and keratinocytes to TRAIL-mediated apoptosis.
abstract: Primary endothelial cells are fully resistant to TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Here, we demonstrate that certain environmental conditions, such as exposure to the widespread allergen nickel, can dramatically increase the susceptibility of naturally resistant primary endothelial cells or keratinocytes to TRAIL-induced apoptosis. While nickel treatment increased surface expression of the apoptosis-inducing TRAIL receptors TRAIL-R1 and TRAIL-R2, it also up-regulated the apoptosis-deficient TRAIL-R4, suggesting that modulation of TRAIL receptor expression alone is unlikely to fully account for the dramatic sensitization effect of nickel. Further analysis of candidate mediators revealed that nickel strongly repressed c-FLIP at mRNA and protein levels. Accordingly, increased activation of Caspase-8 and Caspase-3 following nickel treatment was observed. Importantly, depletion of c-FLIP by RNA interference could largely recapitulate the effect of nickel and sensitize endothelial cells to TRAIL-dependent apoptosis in the absence of nickel pre-treatment. Conversely, ectopic expression of c-FLIP(L) largely protected nickel-treated cells from TRAIL-mediated apoptosis. Our data demonstrate that one key mechanism of sensitization of primary human endothelial cells or keratinocytes is transcriptional down-regulation of c-FLIP. We hypothesize that environmental factors, exemplified by the contact allergen nickel, strongly modulate death ligand sensitivity of endothelial cells and keratinocytes thus influencing vascular and epidermal function and integrity under physiological and pathophysiological conditions.
authors.affiliation: Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt
authors.forename: Mike
authors.initials: M
authors.lastname: Hupe
authors.forename: Nicole
authors.initials: N
authors.lastname: Endres
authors.forename: Badrinarayanan
authors.initials: B
authors.lastname: Raghavan
authors.forename: Shyam
authors.initials: S
authors.lastname: Kavuri
authors.forename: Peter
authors.initials: P
authors.lastname: Geserick
authors.forename: Matthias
authors.initials: M
authors.lastname: Goebeler
authors.forename: Martin
authors.initials: M
authors.lastname: Leverkus
mesh_terms: D000485:Allergens / Q000276:immunology* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009532:Nickel / Q000276:immunology* / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D000485:Allergens; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D009532:Nickel; D053148:Caspase 3; D053181:Caspase 8