Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Stefania Vetrano, Victoria A. Ploplis, Emanuela Sala, Mayra Sandoval-Cooper, Deborah L. Donahue, Carmen Correale, Vincenzo Arena, Antonino Spinelli, Alessandro Repici, Alberto Malesci, Francis J. Castellino, Silvio Danese

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)19830-19835
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number49
DOIs
Publication statusPublished - Dec 6 2011

Keywords

  • DSS-induced colitis
  • Intestinal barrier integrity
  • Intestinal permeability and tight junction proteins

ASJC Scopus subject areas

  • General

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