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Activation of Endothelial Cell Protease Activated Receptor 1 by the Protein C Pathway
Matthias Riewald,1Ramona J. Petrovan,1Aaron Donner,1Barbara M. Mueller,2Wolfram Ruf1*
The coagulant and inflammatory exacerbation in sepsis
is counterbalanced by the protective protein C (PC) pathway. ActivatedPC (APC) was shown to use the endothelial cell PC receptor (EPCR)as a
coreceptor for cleavage of protease activated receptor 1(PAR1) on
endothelial cells. Gene profiling demonstrated thatPAR1 signaling
could account for all APC-induced protective genes,including the
immunomodulatory monocyte chemoattractant protein-1(MCP-1), which was
selectively induced by activation of PAR1,but not PAR2. Thus, the
prototypical thrombin receptor is thetarget for EPCR-dependent APC
signaling, suggesting a role forthis receptor cascade in protection
from sepsis.
1 Department of Immunology, C204, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Division of Cancer Biology, La Jolla
Institute for Molecular Medicine, 4570 Executive Drive, San Diego, CA
92121, USA.
*
To whom correspondence should be addressed. E-mail:
ruf{at}scripps.edu
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Blood
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Proteinase-Activated Receptors: Transducers of Proteinase-Mediated Signaling in Inflammation and Immune Response.
M. Steinhoff, J. Buddenkotte, V. Shpacovitch, A. Rattenholl, C. Moormann, N. Vergnolle, T. A. Luger, and M. D. Hollenberg (2005)
Endocr. Rev.
26, 1-43
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Fibrin(ogen)-{alpha}M{beta}2 Interactions Regulate Leukocyte Function and Innate Immunity In Vivo.
Gene Expression Profiling of Inflamed Human Endothelial Cells and Influence of Activated Protein C.
N. Franscini, E. B. Bachli, N. Blau, M.-S. Leikauf, A. Schaffner, and G. Schoedon (2004)
Circulation
110, 2903-2909
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A role for thrombin in liver fibrosis.
J G. Duplantier, L Dubuisson, N Senant, G Freyburger, I Laurendeau, J-M Herbert, A Desmouliere, and J Rosenbaum (2004)
Gut
53, 1682-1687
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A Protein C Deficiency Exacerbates Inflammatory and Hypotensive Responses in Mice During Polymicrobial Sepsis in a Cecal Ligation and Puncture Model.
J. G. Ganopolsky and F. J. Castellino (2004)
Am. J. Pathol.
165, 1433-1446
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APC stripped bare.
R. J. S. Preston and D. A. Lane (2004)
Blood
104, 1595-1596
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Activated protein C variants with normal cytoprotective but reduced anticoagulant activity.
L. O. Mosnier, A. J. Gale, S. Yegneswaran, and J. H. Griffin (2004)
Blood
104, 1740-1744
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Autoantibodies against EPCR are found in antiphospholipid syndrome and are a risk factor for fetal death.
V. Hurtado, R. Montes, J.-C. Gris, M. L. Bertolaccini, A. Alonso, M. A. Martinez-Gonzalez, M. A. Khamashta, K. Fukudome, D. A. Lane, and J. Hermida (2004)
Blood
104, 1369-1374
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Thrombomodulin-Protein C-EPCR System: Integrated to Regulate Coagulation and Inflammation.
M. V. de Wouwer, D. Collen, and E. M. Conway (2004)
Arterioscler Thromb Vasc Biol
24, 1374-1383
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Activated Protein C Induces Endothelial Cell Proliferation by Mitogen-Activated Protein Kinase Activation In Vitro and Angiogenesis In Vivo.
M. Uchiba, K. Okajima, Y. Oike, Y. Ito, K. Fukudome, H. Isobe, and T. Suda (2004)
Circ. Res.
95, 34-41
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Protease-Activated Receptors (PAR1 and PAR2) Contribute to Tumor Cell Motility and Metastasis.
X. Shi, B. Gangadharan, L. F. Brass, W. Ruf, and B. M. Mueller (2004)
Mol. Cancer Res.
2, 395-402
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Bidirectional Relation Between Inflammation and Coagulation.
M. Levi, T. van der Poll, and H. R. Buller (2004)
Circulation
109, 2698-2704
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Protease-activated Receptor 2-dependent Phosphorylation of the Tissue Factor Cytoplasmic Domain.
