title: c-FLIP protects eosinophils from TNF-α-mediated cell death in vivo.
abstract: Understanding the signals that regulate eosinophil survival and death is critical to developing new treatments for asthma, atopy, and gastrointestinal disease. Previous studies suggest that TNF-α stimulation protects eosinophils from apoptosis, and this TNF-α-mediated protection is mediated by the upregulation of an unknown protein by NF-κB. Here, we show for the first time that eosinophils express the caspase 8-inhibitory protein c-FLIP, and c-FLIP expression is upregulated upon TNF-α stimulation. Considering that c-FLIP expression is regulated by NF-κB, we hypothesized that c-FLIP might serve as the "molecular switch" that converts TNFRI activation to a pro-survival signal in eosinophils. Indeed, we found that one c-FLIP isoform, c-FLIPL, is required for mouse eosinophil survival in the presence of TNF-α both in vitro and in vivo. Importantly, our results suggest c-FLIP as a potential therapeutic target for the treatment of eosinophil-mediated disease.
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Claire
authors.initials: C
authors.lastname: Gordy
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Heather
authors.initials: H
authors.lastname: Pua
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: You-Wen
authors.initials: YW
authors.lastname: He
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005838:Genotype; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha