Activation of Endothelial Cell Protease Activated Receptor 1 by the Protein C Pathway
Matthias Riewald,1
Ramona J. Petrovan,1
Aaron Donner,1
Barbara M. Mueller,2
Wolfram Ruf1*
The coagulant and inflammatory exacerbation in sepsis
is counterbalanced by the protective protein C (PC) pathway. Activated PC (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 that PAR1 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 the target for EPCR-dependent APC
signaling, suggesting a role for this 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
