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Blood, 15 July 2008, Vol. 112, No. 2, pp. 340-349. Prepublished online as a Blood First Edition Paper on March 13, 2008; DOI 10.1182/blood-2007-10-119552. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-10-119552v1 112/2/340    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 Stefanescu, R. Articles by Laurence, J. Search for Related Content PubMed PubMed Citation Articles by Stefanescu, R. Articles by Laurence, J. 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 Synergistic interactions between interferon- and TRAIL modulate c-FLIP in endothelial cells, mediating their lineage-specific sensitivity to thrombotic thrombocytopenic purpura plasma–associated apoptosis Radu Stefanescu1, Dustin Bassett1, Rozbeh Modarresi1, Francisco Santiago1, Mohamad Fakruddin2, and Jeffrey Laurence1 1 Department of Medicine, Division of Hematology-Oncology, Weill Medical College–Cornell University, New York, NY; and 2 Aeras Global TB Vaccine Foundation, Rockville, MD Microvascular endothelial cell (MVEC) injury coupled to progression of platelet microthrombi facilitated by ADAMTS13 deficiency is characteristic of idiopathic and HIV-linked thrombotic thrombocytopenic purpura (TTP). Cytokines capable of inducing MVEC apoptosis in vitro are up-regulated in both TTP and HIV infection. However, the concentrations of these cytokines required to elicit EC apoptosis in vitro are 2- to 3-log–fold greater than present in patient plasmas. We report that clinically relevant levels of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and interferon (IFN)– act in synergy to induce apoptosis in dermal MVECs, but have no effect on large-vessel ECs or pulmonary MVECs. This reflects the tissue distribution of TTP lesions in vivo. Sensitivity to TTP plasma or TRAIL plus IFN- is paralleled by enhanced ubiquitination of the caspase-8 regulator cellular FLICE-like inhibitory protein (c-FLIP), targeting it for proteasome degradation. c-FLIP silencing with anti-FLIP short interfering RNA (siRNA) in pulmonary MVECs rendered them susceptible to TTP plasma– and cytokine-mediated apoptosis, while up-regulation of c-FLIP by gene transfer partially protected dermal MVECs from such injury. TTP plasma–mediated apoptosis appears to involve cytokine-induced acceleration of c-FLIP degradation, sensitizing cells to TRAIL-mediated caspase-8 activation and cell death. Suppression of TRAIL or modulation of immunoproteasome activity may have therapeutic relevance in TTP. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Endothelial cells are not all alike Hau C. Kwaan Blood 2008 112: 218. [Full Text] [PDF]

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