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: Diana Panayotova-Dimitrova, Maria Feoktistova, Michaela Ploesser, Beate Kellert, Mike Hupe, Sebastian Horn, Roman Makarov, Federico Jensen, Stefan Porubsky, Astrid Schmieder, Ana Claudia Zenclussen, Alexander Marx, Andreas Kerstan, Peter Geserick, You-Wen He, Martin Leverkus
• Journal: Cell reports (Cell Rep) Vol. 5 Issue 2 Pg. 397-408 (Oct 31 2013) ISSN: 2211-1247 [Electronic] United States
• PMID: 24209745 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CASP8 and FADD-Like Apoptosis Regulating Protein
• Tumor Necrosis Factor-alpha
• Caspase 8

Topics

• Animals
• Apoptosis (drug effects)
• CASP8 and FADD-Like Apoptosis Regulating Protein (deficiency, genetics, metabolism)
• Caspase 8 (genetics, metabolism)
• Cells, Cultured
• Homeostasis
• Keratinocytes (cytology, drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Skin (metabolism, pathology)
• Tumor Necrosis Factor-alpha (pharmacology)