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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 (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 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 Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 3, 2008 Accepted July 24, 2008 CD40, an upstream master switch for endothelial cell activation uncovered by RNAi-coupled transcriptional profiling Raquel Pluvinet, Rut Olivar, Jerzy Krupinski, Inmaculada Herrero-Fresneda, Anna Luque, Joan Torras, Josep M. Cruzado, Josep M. Grinyo, Lauro Sumoy, and Josep M. Aran* Medical and Molecular Genetics Center, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain Department of Neurology, Stroke Unit, HUB-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain Laboratory of Nephrology, Medicine Department, HUB-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain Bioinformatics and Genomics Program, CRG-UPF, Barcelona, Spain * Corresponding author; email: jaran{at}idibell.org. The CD40-CD154 dyad seems to play a prominent role fostering the immune-inflammatory response triggered by endothelial cell (EC)-T cell communication. To comprehensively delineate the involvement of CD40 (TNFRSF5) in EC activation, we combined RNAi-mediated CD40 knock-down 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, among others, of the major pro-inflammatory 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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