title: Caspase-8 prevents sustained activation of NF-kappaB in monocytes undergoing macrophagic differentiation.
abstract: Caspases have demonstrated several nonapoptotic functions including a role in the differentiation of specific cell types. Here, we show that caspase-8 is the upstream enzyme in the proteolytic caspase cascade whose activation is required for the differentiation of peripheral-blood monocytes into macrophages. On macrophage colony-stimulating factor (M-CSF) exposure, caspase-8 associates with the adaptor protein Fas-associated death domain (FADD), the serine/threonine kinase receptor-interacting protein 1 (RIP1) and the long isoform of FLICE-inhibitory protein FLIP. Overexpression of FADD accelerates the differentiation process that does not involve any death receptor. Active caspase-8 cleaves RIP1, which prevents sustained NF-kappaB activation, and activates downstream caspases. Together these data identify a role for caspase-8 in monocytes undergoing macrophagic differentiation, that is, the enzyme activated in an atypical complex down-regulates NF-kappaB activity through RIP1 cleavage.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U517, Dijon, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Rébé
authors.forename: Séverine
authors.initials: S
authors.lastname: Cathelin
authors.forename: Sophie
authors.initials: S
authors.lastname: Launay
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Filomenko
authors.forename: Laurent
authors.initials: L
authors.lastname: Prévotat
authors.forename: Coralie
authors.initials: C
authors.lastname: L'Ollivier
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Gyan
authors.forename: Olivier
authors.initials: O
authors.lastname: Micheau
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Anne
authors.initials: A
authors.lastname: Dubart-Kupperschmitt
authors.forename: Michaëla
authors.initials: M
authors.lastname: Fontenay
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
mesh_terms: D053181:Caspase 8 / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology*; D009000:Monocytes / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: C119724:AGFG1 protein, human; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D016173:Macrophage Colony-Stimulating Factor; D053181:Caspase 8