Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation
| Autor: | Victoria A. Ploplis, Stefania Vetrano, Deborah L. Donahue, Emanuela Sala, Alberto Malesci, Mayra J. Sandoval-Cooper, Antonino Spinelli, Alessandro Repici, Francis J. Castellino, Vincenzo Arena, Silvio Danese, Carmen Correale |
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| Přispěvatelé: | Vetrano, S, Ploplis, Va, Sala, E, Sandoval-Cooper, M, Donahue, Dl, Correale, C, Arena, V, Spinelli, A, Repici, A, Malesci, A, Castellino, Fj, Danese, S |
| Rok vydání: | 2011 |
| Předmět: |
Male
tight junctions colitis Gene Expression knockout receptors membrane proteins protein C Mice zonula occludens-1 protein animals Intestinal mucosa antigens Intestinal Mucosa humans Cells Cultured DSS-induced colitis Mice Knockout Endothelial protein C receptor intestinal barrier integrity intestines Multidisciplinary Tight junction Reverse Transcriptase Polymerase Chain Reaction Endothelial Protein C Receptor Biological Sciences Colitis Immunohistochemistry CD Cell biology Intestines animals reverse transcriptase polymerase chain reaction cell surface immunohistochemistry medicine.symptom signal transduction Signal Transduction anticoagulants mice Mice Transgenic Receptors Cell Surface Inflammation Biology Thrombomodulin inflammatory bowel diseases Tight Junctions Proinflammatory cytokine male Antigens CD medicine Animals Humans inbred C57BL Interleukin 8 cultured transgenic Intestinal permeability Interleukin-6 intestinal permeability and tight junction proteins interleukin-6 Interleukin-8 interleukin-8 Anticoagulants Membrane Proteins Epithelial Cells Inflammatory Bowel Diseases Phosphoproteins medicine.disease epithelial cells Mice Inbred C57BL intestinal mucosa Immunology Zonula Occludens-1 Protein gene expression cells Caco-2 Cells phosphoproteins Protein C |
| Zdroj: | Proceedings of the National Academy of Sciences. 108:19830-19835 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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