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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anticoagulants / pharmacology
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Antigens, CD / genetics
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Antigens, CD / metabolism
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Caco-2 Cells
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Cells, Cultured
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Colitis / genetics*
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Colitis / metabolism
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Endothelial Protein C Receptor
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism*
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Epithelial Cells / pathology
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Gene Expression
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Humans
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Immunohistochemistry
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Inflammatory Bowel Diseases / genetics*
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Inflammatory Bowel Diseases / metabolism
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Interleukin-6 / metabolism
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Interleukin-8 / metabolism
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / metabolism
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Intestinal Mucosa / pathology
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Intestines / pathology
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein C / genetics*
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Protein C / pharmacology
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Protein C / physiology
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics
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Signal Transduction / physiology
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Tight Junctions / drug effects
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Tight Junctions / metabolism
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Zonula Occludens-1 Protein
Substances
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Anticoagulants
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Antigens, CD
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Endothelial Protein C Receptor
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Interleukin-6
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Interleukin-8
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Membrane Proteins
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PROCR protein, human
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Phosphoproteins
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Protein C
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Receptors, Cell Surface
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TJP1 protein, human
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Tjp1 protein, mouse
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Zonula Occludens-1 Protein