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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1442-1450.
Prepublished online as a Blood First Edition Paper on October 17, 2006; DOI 10.1182/blood-2006-03-011585.
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HEMATOPOIESIS
Caspase-8 prevents sustained activation of NF- B in monocytes undergoing macrophagic differentiation
Cédric Rébé1,2,
Séverine Cathelin1,2,
Sophie Launay1,2,
Rodolphe Filomenko1,3,
Laurent Prévotat1,3,
Coralie L'Ollivier1,2,4,
Emmanuel Gyan5,6,
Olivier Micheau1,2,
Steven Grant7,
Anne Dubart-Kupperschmitt5,
Michaëla Fontenay5,6, and
Eric Solary1,2,4
1 Institut National de la Santé et de la Recherche Médicale (INSERM) U517, Dijon, France;
2 Institut Fédératif de Recherche (IFR) 100, University of Burgundy, Dijon, France;
3 Ecole Pratique des Hautes Etudes (EPHE), Faculty of Medicine, Dijon cedex, France;
4 Centre Hospitalier Universitaire, Dijon cedex, France;
5 INSERM U567, Institut Cochin, Paris, France;
6 Department of Hematology, Cochin Hospital, Paris, France; and the
7 Department of Medicine and Biochemistry, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA
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- B 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- B activity through RIP1 cleavage.

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