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Blood, 1 November 2008, Vol. 112, No. 9, pp. 3624-3637. Prepublished online as a Blood First Edition Paper on July 31, 2008; DOI 10.1182/blood-2008-03-143305. This Article Full Text Full Text (PDF) Supplemental Methods, Tables, and Figures All Versions of this Article: blood-2008-03-143305v1 112/9/3624    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Pluvinet, R. Articles by Aran, J. M. Search for Related Content PubMed PubMed Citation Articles by Pluvinet, R. Articles by Aran, J. M. Related Collections Hemostasis, Thrombosis, and Vascular Biology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY CD40: an upstream master switch for endothelial cell activation uncovered by RNAi-coupled transcriptional profiling Raquel Pluvinet1, Rut Olivar1, Jerzy Krupinski2, Inmaculada Herrero-Fresneda3, Anna Luque2, Joan Torras3, Josep M. Cruzado3, Josep M. Grinyó3, Lauro Sumoy4, and Josep M. Aran1 1 Medical and Molecular Genetics Center, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona; 2 Department of Neurology, Stroke Unit and 3 Laboratory of Nephrology, Medicine Department, Hospital Universitari de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Barcelona; and 4 Bioinformatics and Genomics Program, Centre de Regulació Genòmica (CRG)–Universitat Pompeu Fabra (UPF), Barcelona, Spain The CD40-CD154 dyad seems to play a prominent role fostering the immune-inflammatory response triggered by endothelial cell (EC)–T-cell communication. To delineate comprehensively the involvement of CD40 (TNFRSF5) in EC activation, we combined RNAi-mediated CD40 knockdown with comparative genome-wide transcriptional profiling of ECs interacting with (CD154+) T cells. We report the initiation of a profound stress response in ECs upon CD40-CD154 engagement through early up-regulation of, among others, the major proinflammatory NF-B and MAPK/SAPK pathways and their associated transcription factors. Moreover, we have identified novel genes regulated through the CD40-CD154 interaction, and pathways previously unrecognized to be induced by CD40 signaling in ECs. Thus, we document a significant down-regulation of endothelial APLN by CD40-CD154 interaction, TNF/IFN exposure, and in immune-inflammatory pathologies, which could lead to hemodynamic dysfunction. Conversely, CD40-mediated up-regulation of the viral immune surveillance system, notably TLR3, IFIH1, RIG-I, and RNASEL, establishes a reverse link from adaptive to innate immunity in ECs. Moreover, systematic enrichment analysis substantiates endothelial CD40 involvement in the transcriptional regulation of gene networks associated with adhesion and motility, immunity, cell fate control, hemostasis, and metabolism. Our study also highlights the anti-inflammatory potential of RNAi-mediated CD40 inhibition, and the relevance of CD40 signaling for therapeutic intervention. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: CD40: Lord of the endothelial cell Richard P. Phipps Blood 2008 112: 3531-3532. [Full Text] [PDF]

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