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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.
 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.
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