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* Institute of Interdisciplinary Research, Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium;
Department of Medical Chemistry, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium; and
Department of Genetics, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
Extracellular ATP and PGE2 are two cAMP-elevating agents inducing semimaturation of human monocyte-derived dendritic cells (MoDCs). We have extensively compared the gene expression profiles induced by adenosine 5'-O-(3-thiotriphosphate) (ATP
S) and PGE2 in human MoDCs using microarray technology. At 6 h of stimulation, ATPS initiated an impressive expression profile compared with that of PGE2 (1125 genes compared with 133 genes, respectively) but after 24 h the number of genes regulated by ATPS or PGE2 was more comparable. Many target genes involved in inflammation have been identified and validated by quantitative RT-PCR experiments. We have then focused on novel ATPS and PGE2 target genes in MoDCs including CSF-1, MCP-4/CCL13 chemokine, vascular endothelial growth factor-A, and neuropilin-1. ATPS strongly down-regulated CSF-1 receptor mRNA and CSF-1 secretion, which are involved in monocyte and dendritic cell (DC) differentiation. Additionally, ATPS down-regulated several chemokines involved in monocyte and DC migration including CCL2/MCP-1, CCL3/MIP-1
, CCL4/MIP-1
, CCL8/MCP-2, and CCL13/MCP-4. Interestingly, vascular endothelial growth factor A, a major angiogenic factor displaying immunosuppressive properties, was secreted by MoDCs in response to ATPS, ATP, or PGE2, alone or in synergy with LPS. Finally, flow cytometry experiments have demonstrated that ATPS, ATP, and PGE2 down-regulate neuropilin-1, a receptor playing inter alia an important role in the activation of T lymphocytes by DCs. Our data give an extensive overview of the genes regulated by ATPS and PGE2 in MoDCs and an important insight into the therapeutic potential of ATP- and PGE2-treated human DCs.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by an Action de Recherche Concertée of the Communauté Française de Belgique, by the Belgian Programme on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister’s Office, Federal Service for Science, Technology and Culture, by grants of the Fonds de la Recherche Scientifique Médicale, the Fonds Emile DEFAY, and the LifeSciHealth programme of the European Community (Grant LSHB-2003-503337). N. B., M. H., and F. M. were supported by the Fonds National de la Recherche Scientifique/Fonds pour la Recherche dans l’Industrie et dans l’Agriculture, Belgium. D. C. and F. L. are Research Associate of the Fonds National de la Recherche Scientifique (FNRS).
2 N. B. and M. H. contributed equally to the work.
3 Address correspondence and reprint requests to Dr. Didier Communi, Institute of Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles, Building C (5th floor), Campus Erasme, 808 Route de Lennik, Brussels, Belgium. E-mail address: communid{at}ulb.ac.be
4 Abbreviations used in this paper: DC, dendritic cell; ATPS, adenosine 5'-O-(3-thiotriphosphate); MoDC, monocyte-derived DC; TSP-1, thrombospondin-1; NRP-1, neuropilin-1; qRT-PCR, quantitative RT-PCR; VEGF, vascular endothelial growth factor.
5 The online version of this article contains supplemental material.
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