Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease
Franco Scaldaferri, … , Brian W. Grinnell, Silvio Danese
Franco Scaldaferri, … , Brian W. Grinnell, Silvio Danese
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):1951-1960. https://doi.org/10.1172/JCI31027.
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Research Article Gastroenterology

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

Abstract

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.

Authors

Franco Scaldaferri, Miquel Sans, Stefania Vetrano, Cristina Graziani, Raimondo De Cristofaro, Bruce Gerlitz, Alessandro Repici, Vincenzo Arena, Alberto Malesci, Julian Panes, Brian W. Grinnell, Silvio Danese

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Figure 3

Effect of different cytokines on EPCR and TM expression by HIMECs.

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Effect of different cytokines on EPCR and TM expression by HIMECs. (A) H...
(A) HIMEC monolayers were left untreated (Baseline) or stimulated with TNF-α or IL-10 for 24 hours, after which cells were suspended and EPCR and TM expression measured by flow cytometry. Filled curve represents background signal from the isotype control. Values are representative of 6 separate experiments. Numbers represent the net percentage of positive cells. (B) HIMEC monolayers were left untreated or stimulated with TNF-α for 24 hours, after which supernatants were collected for ELISA measurement of soluble EPCR and TM. Cellular mRNA was extracted for real-time PCR of EPCR and TM message levels. Values are representative of 3 separate experiments. *P < 0.05, **P < 0.01 versus baseline.