Submitted February 6, 2008
Accepted August 1, 2008
cIAP1-dependent TRAF2 degradation regulates the differentiation of monocytes into macrophages and their response to CD40-ligand
Alban Dupoux, Jessy Cartier, Severine Cathelin, Rodolphe Filomenko, Eric Solary, and Laurence Dubrez-Daloz*
Institut National de la Sante et de la Recherche Medicale (INSERM) UMR866, Dijon, France
University of Burgundy; Faculty of Medicine, Institut Federatif de recherche, Dijon, France
* Corresponding author; email: laurence.dubrez-daloz{at}u-bourgogne.fr.
Peripheral blood monocytes are plastic cells that migrate to tissues and differentiate into various cell types including macrophages, dendritic cells and osteoclasts. We have described the migration of cIAP1 (Inhibitor of Apoptosis Protein 1), a member of IAP family of proteins, from the nucleus to the Golgi apparatus in monocytes undergoing differentiation into macrophages. Here, we show that, once in the cytoplasm, cIAP1 is involved in the degradation of the adaptor protein TRAF2 by the proteosomal machinery. Inhibition of cIAP1 prevents the decrease in TRAF2 expression that characterizes macrophage formation. We demonstrate that TRAF2 is initially required for macrophage differentiation as its silencing prevents I
-B
degradation, NFB-B p65 nuclear translocation and the differentiation process. Then, we show that cIAP1 mediated degradation of TRAF2 allows the differentiation process to progress. This degradation is required for the macrophages to be fully functional as TRAF2 overexpression in differentiated cells decreases the c-Jun N-terminal kinase-mediated synthesis and the secretion of pro-inflammatory cytokines such as interleukin-8 and MCP-1 in response to CD40 ligand. We conclude that TRAF2 expression and subsequent degradation are required for the differentiation of monocytes into fully functional macrophages.
