TY - JOUR
T1 - Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation
AU - Vetrano, Stefania
AU - Ploplis, Victoria A.
AU - Sala, Emanuela
AU - Sandoval-Cooper, Mayra
AU - Donahue, Deborah L.
AU - Correale, Carmen
AU - Arena, Vincenzo
AU - Spinelli, Antonino
AU - Repici, Alessandro
AU - Malesci, Alberto
AU - Castellino, Francis J.
AU - Danese, Silvio
PY - 2011/12/6
Y1 - 2011/12/6
N2 - The protein C (PC) pathway is a well-characterized coagulation system. Endothelial PC receptors and thrombomodulin mediate the conversion of PC to its activated form, a potent anticoagulant and anti-inflammatory molecule. Here we show that the PC pathway is expressed on intestinal epithelial cells. The epithelial expression of PC and endothelial PC receptor is down-regulated In patients with inflammatory bowel disease. PC -/-/PC(Tg) mice, expressing only 3% of WT PC, developed spontaneous intestinal inflammation and were prone to severe experimental colitis. These mice also demonstrated spontaneous elevated production of inflammatory cytokines and increased intestinal permeability. Structural analysis of epithelial tight junction molecules revealed that lack of PC leads to decreased JAM-A and claudin-3 expression and an altered pattern of ZO-1 expression. In vitro, treatment of epithelial cells with activated PC led to protection of tight junction disruption induced by TNF-α, and in vivo, topical treatment with activated PC led to mucosal healing and amelioration of colitis. Taken together, these findings demonstrate that the PC pathway is a unique system involved in controlling intestinal homeostasis and inflammation by regulating epithelial barrier function.
AB - The protein C (PC) pathway is a well-characterized coagulation system. Endothelial PC receptors and thrombomodulin mediate the conversion of PC to its activated form, a potent anticoagulant and anti-inflammatory molecule. Here we show that the PC pathway is expressed on intestinal epithelial cells. The epithelial expression of PC and endothelial PC receptor is down-regulated In patients with inflammatory bowel disease. PC -/-/PC(Tg) mice, expressing only 3% of WT PC, developed spontaneous intestinal inflammation and were prone to severe experimental colitis. These mice also demonstrated spontaneous elevated production of inflammatory cytokines and increased intestinal permeability. Structural analysis of epithelial tight junction molecules revealed that lack of PC leads to decreased JAM-A and claudin-3 expression and an altered pattern of ZO-1 expression. In vitro, treatment of epithelial cells with activated PC led to protection of tight junction disruption induced by TNF-α, and in vivo, topical treatment with activated PC led to mucosal healing and amelioration of colitis. Taken together, these findings demonstrate that the PC pathway is a unique system involved in controlling intestinal homeostasis and inflammation by regulating epithelial barrier function.
KW - DSS-induced colitis
KW - Intestinal barrier integrity
KW - Intestinal permeability and tight junction proteins
UR - http://www.scopus.com/inward/record.url?scp=83755195016&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=83755195016&partnerID=8YFLogxK
U2 - 10.1073/pnas.1107140108
DO - 10.1073/pnas.1107140108
M3 - Article
C2 - 22109555
AN - SCOPUS:83755195016
VL - 108
SP - 19830
EP - 19835
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 49
ER -