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Blood, 1 November 2008, Vol. 112, No. 9, pp. 3531-3532. This Article Full Text (PDF) 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 Phipps, R. P. Search for Related Content PubMed PubMed Citation Articles by Phipps, R. P. Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Next Article  HEMOSTASIS Comment on Pluvinet et al, page 3624 CD40: Lord of the endothelial cell Richard P. Phipps UNIVERSITY OF ROCHESTER CD40, a membrane-associated receptor, is a key activator of immune and vascular cells. In this issue of Blood, Pluvinet and colleagues reveal new features of human endothelial cells activated through CD40 that include inflammatory, thrombotic, and innate immune effects. CD40 has a rich history as a prominent immune cell activator.1 CD40 is best known as the key mediator of B lymphocyte immunoglobulin class switch. It also serves as a major activator of antigen-presenting cells, such as macrophages and dendritic cells. More recently, it was discovered that CD40 is expressed on many types of human cells including tissue structural cells, such as fibroblasts, epithelial cells, and endothelial cells.2,3 On these cells, like classic immune cells, CD40 also serves as a major mediator of cell activation. For example, on endothelial cells, engagement of CD40 incites the production of adhesion molecules, cytokines, chemokines, and inflammatory mediators important for wound healing.3,4 View larger version (116K): [in this window] [in a new window]   Interaction of activated T cells and endothelial cells via the CD40. CD40L pathway leads to endothelial cell activation. In addition to the known proinflammatory mediators induced by this pathway, many potential new targets were also identified. Also discovered were mediators of hemodynamic dysfunction and coordinated enhancement of innate antiviral defenses.   The natural ligand for CD40 is called CD40 ligand (CD40L; officially termed CD154) and can be expressed, after activation, on the surface of several cell types, including T lymphocytes and platelets.1,4,5 There is much interest in endothelial cell activation by CD40 ligand due to the potential consequences of this event, such as atherosclerotic progression, chronic inflammation, and organ rejection. Previously, blocking CD40 ligand was a therapeutic target in certain inflammatory diseases and in organ rejection as a pathway to inducing immune tolerance. However, due to human platelet expression of CD40L, thromboembolic events occurred in early clinical trials, setting back CD40L as an immune system target. However, these unanticipated side effects resulted in CD40 being vigorously pursued as a means to attenuate unwanted endothelial and other cell activation. In this issue of Blood, Pluvinet et al focus on the down-stream events triggered by T-cell delivery of CD40L to several types of human endothelial cells. Two complementary approaches were used to find and validate the down-stream consequences of CD40 signaling in endothelial cells. First, they used a human T-cell line that highly expressed CD40L to activate CD40-bearing human endothelial cells. Using genome wide transcriptional profiling, they identified many new genes not thought to be regulated by the CD40-CD40L pathway. Some of these were further validated using other methods, such as Northern blotting, Western blotting, immunohistochemistry, and a preclinical animal model of organ rejection. A second strength of their approach was the use of RNAi to knock down expression of CD40 in endothelial cells, further proving the importance of CD40 as a master switch that sets in motion a host of coordinated events. Their work on CD40 signaling revealed the rapid and global response of endothelial cells after activation by T cells, including coordinated kinase and transcription factor changes impacting on inflammation, cell motility, and vascular tone. Two major findings of particular interest are highlighted in their article. The first involves a vasoactive peptide called apelin,6 which was highly down-regulated in endothelial cells after CD40-CD40L interaction. Apelin appears to play an important role as a blood vessel dilator and may have cardioprotective effects. The authors also postulate that down-regulation of endothelial apelin in an inflamed transplanted kidney is a major factor in dysregulation of fluid homeostasis associated with renal transplant rejection. The second highlighted finding is that CD40-stimulated endothelial cells up-regulated genes involved in host defense against viruses. These genes include those involved in detecting viral RNA, such as TLR3, and in further activation of endothelial cells by up-regulating the IFN receptor. IFN binding to its receptor up-regulates CD40 expression, constituting an amplification pathway. Also of interest was the finding that certain proteins that permit viral entry were down-regulated by CD40. These include CXCR4, a chemokine receptor important for HIV entry into cells. These coordinated events appear to amplify innate immunity via the T-cell arm of adaptive immunity. The work of Pluvinet et al provides much new information on human endothelial cell activation by CD40. Many of the genes and pathways identified herein require further validation. Moreover, endothelial cells are increasingly recognized as being diverse and differ from organ to organ and even within a single organ.7 Endothelial cell activation via delivery of CD40L from T cells may differ from other sources, such as platelets or microparticles. Therefore, it is important to discover the role of CD40L-bearing cells in different diseases. These unknowns aside, the door is open to tackling the new exciting targets of down-stream CD40 signaling in endothelial cells. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Banchereau J, Bazan F, Blanchard D, et al. The CD40 antigen and its ligand. Annu Rev Immunol. 1994;12:881–922.[CrossRef][Medline] [Order article via Infotrieve] Fries KM, Sempowski GD, Phipps RP, et al. CD40 expression by human fibroblasts. Clin Immunol Immunopathol. 1995;77:42–51.[CrossRef][Medline] [Order article via Infotrieve] Schonbeck U, Libby P. CD40 signaling and plaque instability. Circ Res. 2001;89:1092–1103.[Abstract/Free Full Text] Phipps RP, Koumas L, Kaufman J, et al. The CD40-CD40 ligand system: A potential therapeutic target in atherosclerosis. Curr Opin Invest Drugs. 2001;2:773–777.[Medline] [Order article via Infotrieve] Henn V, Slupsky JR, Grafe M, et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature. 1998;5:591–594.[CrossRef] Lee DK, George SR, O'Dowd BF. Unravelling the roles of the apelin system: prospective therapeutic applications in heart failure and obesity. Trends Pharmacol Sci. 2006;27:190–194.[CrossRef][Medline] [Order article via Infotrieve] Aird WC. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res. 2007;100:158–173.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: 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. Grinyó, Lauro Sumoy, and Josep M. Aran Blood 2008 112: 3624-3637. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) 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 Phipps, R. P. Search for Related Content PubMed PubMed Citation Articles by Phipps, R. P. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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