Inflammation and Apoptosis in Clostridium difficile Enteritis Is Mediated by PGE2 Up-Regulation of Fas Ligand
| Autor: | J. Thomas Lamont, Ho Kim, Sang Hoon Rhee, Charalabos Pothoulakis |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Male
Fas Ligand Protein Colon Enterocyte Bacterial Toxins Clostridium difficile toxin A Apoptosis Inflammation Mice SCID Biology medicine.disease_cause Dinoprostone Fas ligand Cell Line Enteritis Enterotoxins Mice medicine Animals Humans Receptors Prostaglandin E Secretion Mice Knockout Mice Inbred C3H Hepatology Clostridioides difficile Toxin NF-kappa B Gastroenterology Ileitis medicine.disease Receptors Prostaglandin E EP1 Subtype Molecular biology Coculture Techniques Up-Regulation medicine.anatomical_structure Cyclooxygenase 2 Immunology lipids (amino acids peptides and proteins) medicine.symptom |
| Zdroj: | Gastroenterology. 133:875-886 |
| ISSN: | 0016-5085 |
| DOI: | 10.1053/j.gastro.2007.06.063 |
| Popis: | Background & Aims:Clostridium difficile toxin A causes acute inflammation and fluid secretion in experimental animals and patients with C difficile infection. We previously reported that toxin A increased cyclooxygenase-2/prostaglandin E2 (PGE2) expression and apoptosis in human colonocytes. Here, we assessed the role of secreted PGE2 in inflammation and enterocyte apoptosis in toxin A enteritis. Methods: Effects of PGE2 and PGE2 blockade on toxin A-induced apoptosis of human colonocytes (NCM460) and of PGE2 or toxin A on the Fas ligand (FasL) induction were analyzed by flow cytometry and Western blot. Functional activity of elevated FasL on colonocytes was assessed by coculture of colonocytes with Fas bearing Jurkat T cells. The involvement of PGE2-dependent Fas/FasL activation in toxin A enteritis was further assessed in either scid or FasL and Fas deficient mice. Results: Inhibition of cyclooxygenase-2 by NS-398 and of PGE2 using a blocking antibody markedly attenuated apoptosis in colonocytes exposed to toxin A. Enhanced expression and release of FasL followed PGE2 or toxin A exposure in vivo and in vitro and also was significantly attenuated by treatment with NS-398 and PGE2 blocking antibody. PGE2 acting through an EP1 receptor activated nuclear factor-κB, which induced transcription of FasL. Toxin A enteritis was accompanied by increased cellular infiltration, fluid secretion, and mucosal damage in control mice, but this response was markedly reduced in both Fas−/− and FasL−/− mice. Conclusions: Toxin A enteritis involves release of PGE2, which activates the Fas/FasL system, causing enterocyte apoptosis and inflammation. |
| Databáze: | OpenAIRE |
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