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Blood, 15 March 2007, Vol. 109, No. 6, pp. 2453-2460. Prepublished online as a Blood First Edition Paper on November 9, 2006; DOI 10.1182/blood-2006-08-040444. This Article Full Text (PDF) All Versions of this Article: blood-2006-08-040444v1 109/6/2453    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Viemann, D. Articles by Roth, J. Search for Related Content PubMed PubMed Citation Articles by Viemann, D. Articles by Roth, J. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 11, 2006 Accepted October 30, 2006 MRP8/MRP14 impairs endothelial integrity and induces a caspase-dependent and -independent cell death program Dorothee Viemann, Katarzyna Barczyk, Thomas Vogl, Ute Fischer, Cord Sunderkotter, Klaus Schulze-Osthoff, and Johannes Roth* Department of Pediatrics, University Hospital Muenster, Muenster, Germany Institute of Experimental Dermatology, University of Muenster, Muenster, Germany Institute of Molecular Medicine, University of Dusseldorf, Dusseldorf, Germany Department of Dermatology, University of Muenster, Muenster, Germany Interdisciplinary Center of Clinical Research, University of Muenster, Muenster, Germany * Corresponding author; email: rothj{at}uni-muenster.de. Activated phagocytes express considerable amounts of MRP8 and MRP14, two calcium-binding S100-proteins forming stable heterodimers that are specifically secreted at inflammatory sites in many diseases. We previously reported that treatment of human microvascular endothelial cells with purified MRP8/MRP14 leads to loss of endothelial cell-contacts. In this study, we demonstrate that MRP8/MRP14-complexes furthermore trigger cell death of endothelial cells after the onset of cell detachment. Morphological analysis of dying endothelial cells revealed characteristic features of both, apoptosis and necrosis. Furthermore, MRP8/MRP14 induced apoptotic caspase-9 and - 3 activation, DNA fragmentation and membrane phosphatidylserine exposure in target cells. These events were independent of death receptor signaling and in part controlled by a mitochondrial pathway. Consistently, overexpression of anti-apoptotic Bcl-2 abrogated caspase activation and externalization of phosphatidylserine, however, MRP8/MRP14 still induced plasma membrane damage and even DNA fragmentation. Thus, our results demonstrate that MRP8/MRP14 triggers cell death via caspase-dependent as well as -independent mechanisms. Excessive release of cytotoxic MRP8/MRP14 by activated phagocytes might therefore present an important molecular pathomechanism contributing to endothelial damage during vasculitis and other inflammatory diseases. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Frosch and J. Roth New insights in systemic juvenile idiopathic arthritis--from pathophysiology to treatment Rheumatology, February 1, 2008; 47(2): 121 - 125. [Abstract] [Full Text] [PDF]

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