title: cFLIP regulates skin homeostasis and protects against TNF-induced keratinocyte apoptosis.
abstract: 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 cFLIPfl/fl-K14CreERtam 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.
authors.forename: Diana
authors.initials: D
authors.lastname: Panayotova-Dimitrova
authors.forename: Maria
authors.initials: M
authors.lastname: Feoktistova
authors.forename: Michaela
authors.initials: M
authors.lastname: Ploesser
authors.forename: Beate
authors.initials: B
authors.lastname: Kellert
authors.forename: Mike
authors.initials: M
authors.lastname: Hupe
authors.forename: Sebastian
authors.initials: S
authors.lastname: Horn
authors.forename: Roman
authors.initials: R
authors.lastname: Makarov
authors.forename: Federico
authors.initials: F
authors.lastname: Jensen
authors.forename: Stefan
authors.initials: S
authors.lastname: Porubsky
authors.forename: Astrid
authors.initials: A
authors.lastname: Schmieder
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Zenclussen
authors.forename: Alexander
authors.initials: A
authors.lastname: Marx
authors.forename: Andreas
authors.initials: A
authors.lastname: Kerstan
authors.forename: Peter
authors.initials: P
authors.lastname: Geserick
authors.forename: You-Wen
authors.initials: YW
authors.lastname: He
authors.forename: Martin
authors.initials: M
authors.lastname: Leverkus
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D006706:Homeostasis; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D014409:Tumor Necrosis Factor-alpha; D053181:Caspase 8