Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease

Endothelial protein C receptor (EPCR) and thrombomodulin (TM) are expressed at high levels in the resting microvasculature and convert protein C (PC) into its activated form, which is a potent anticoagulant and antiinflammatory molecule. Here we provide evidence that in Crohn disease (CD) and ulcera...

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Bibliographic Details
Published in:The Journal of clinical investigation Vol. 117; no. 7; pp. 1951 - 1960
Main Authors: Scaldaferri, Franco, Sans, Miquel, Vetrano, Stefania, Graziani, Cristina, De Cristofaro, Raimondo, Gerlitz, Bruce, Repici, Alessandro, Arena, Vincenzo, Malesci, Alberto, Panes, Julian, Grinnell, Brian W., Danese, Silvio
Format: Journal Article
Language:English
Published: United States American Society for Clinical Investigation 01.07.2007
Subjects:
Animals
Antigens, CD - metabolism
Biomedical research
Cell Adhesion - drug effects
Cells, Cultured
Chemokines - biosynthesis
Colorectal diseases
Down-Regulation
Endothelial Protein C Receptor
Endothelium - pathology
Gastrointestinal diseases
Humans
Immunohistochemistry
Inflammation
Inflammation - metabolism
Inflammation - pathology
Inflammatory bowel disease
Inflammatory Bowel Diseases - metabolism
Inflammatory Bowel Diseases - pathology
Intercellular Adhesion Molecule-1 - metabolism
Leukocytes - cytology
Mice
Microcirculation - metabolism
Microcirculation - pathology
Protein C
Protein C - metabolism
Protein C - pharmacology
Receptors, Cell Surface - metabolism
Signal Transduction - drug effects
Thrombomodulin - metabolism
Tumor Necrosis Factor-alpha - pharmacology
Vascular Cell Adhesion Molecule-1 - metabolism
United States
ISSN:0021-9738, 1558-8238
Online Access:Get full text
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Summary:Endothelial protein C receptor (EPCR) and thrombomodulin (TM) are expressed at high levels in the resting microvasculature and convert protein C (PC) into its activated form, which is a potent anticoagulant and antiinflammatory molecule. Here we provide evidence that in Crohn disease (CD) and ulcerative colitis (UC), the 2 major forms of inflammatory bowel disease (IBD), there was loss of expression of endothelial EPCR and TM, which in turns caused impairment of PC activation by the inflamed mucosal microvasculature. In isolated human intestinal endothelial cells, administration of recombinant activated PC had a potent antiinflammatory effect, as demonstrated by downregulated cytokine-dependent cell adhesion molecule expression and chemokine production as well as inhibited leukocyte adhesion. In vivo, administration of activated PC was therapeutically effective in ameliorating experimental colitis as evidenced by reduced weight loss, disease activity index, and histological colitis scores as well as inhibited leukocyte adhesion to the inflamed intestinal vessels. The results suggest that the PC pathway represents a new system crucially involved in governing intestinal homeostasis mediated by the mucosal microvasculature. Restoring the PC pathway may represent a new therapeutic approach to suppress intestinal inflammation in IBD.
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ISSN:0021-9738
1558-8238
DOI:10.1172/JCI31027