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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
22
pubmed:dateCreated
2005-5-30
pubmed:abstractText
Clostridium difficile toxin A induces acute colitis with neutrophil infiltration and up-regulation of numerous pro-inflammatory mediators, but the contribution of cyclooxygenase-2 (COX-2) induction in this infection is unknown. We report here that toxin A induces expression of COX-2 and secretion of prostaglandin E2 (PGE2) in a dose- and time-dependent manner in cultured NCM460 human colonocytes and in human intestinal xenografts. This induction was blocked by SB203580, a p38 MAPK inhibitor, which also decreased the phosphorylation of MSK-1, CREB/ATF-1, and COX-2 promoter activity following toxin A stimulation. Gel shift assays indicated that CREB/ATF-1 was the major proteins binding to the COX-2-CRE. Moreover, colonocytes exposed to toxin A produced reactive oxygen species (ROS), which activated p38 MAPK, MSK-1, and CREB/ATF-1, leading to subsequent COX-2 induction and PGE2 secretion. In intact mice, blockage of p38 MAPK inhibited toxin A-mediated induction of COX-2 in enterocytes as well as lamina propria cells, and significantly blocked the toxin A-induced ileal secretion of fluid and PGE2. Furthermore, a selective COX-2 inhibitor also diminished toxin A-associated ileal fluid and PGE2 secretion. The main signaling pathway for toxin A induction of human COX-2 involves ROS-mediated activation of p38 MAPK, MSK-1, CREB, and ATF-1. Toxin A triggers ileal inflammation and secretion of fluid via COX-2 induction and release of PGE2.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Bacterial Toxins, http://linkedlifedata.com/resource/pubmed/chemical/Cyclic AMP, http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase 2, http://linkedlifedata.com/resource/pubmed/chemical/Dinoprostone, http://linkedlifedata.com/resource/pubmed/chemical/Enterotoxins, http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Imidazoles, http://linkedlifedata.com/resource/pubmed/chemical/Intramolecular Oxidoreductases, http://linkedlifedata.com/resource/pubmed/chemical/Luciferases, http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins, http://linkedlifedata.com/resource/pubmed/chemical/N-(2-cyclohexyloxy-4-nitrophenyl)met..., http://linkedlifedata.com/resource/pubmed/chemical/Nitrobenzenes, http://linkedlifedata.com/resource/pubmed/chemical/PTGS2 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Prostaglandin-Endoperoxide Synthases, http://linkedlifedata.com/resource/pubmed/chemical/Pyridines, http://linkedlifedata.com/resource/pubmed/chemical/RNA, http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger, http://linkedlifedata.com/resource/pubmed/chemical/Reactive Oxygen Species, http://linkedlifedata.com/resource/pubmed/chemical/SB 203580, http://linkedlifedata.com/resource/pubmed/chemical/Sulfonamides, http://linkedlifedata.com/resource/pubmed/chemical/p38 Mitogen-Activated Protein..., http://linkedlifedata.com/resource/pubmed/chemical/prostaglandin-E synthase, http://linkedlifedata.com/resource/pubmed/chemical/tcdA protein, Clostridium difficile
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
3
pubmed:volume
280
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
21237-45
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:15767259-Animals, pubmed-meshheading:15767259-Bacterial Toxins, pubmed-meshheading:15767259-Cell Line, pubmed-meshheading:15767259-Colon, pubmed-meshheading:15767259-Cyclic AMP, pubmed-meshheading:15767259-Cyclooxygenase 2, pubmed-meshheading:15767259-Dinoprostone, pubmed-meshheading:15767259-Dose-Response Relationship, Drug, pubmed-meshheading:15767259-Electrophoresis, Polyacrylamide Gel, pubmed-meshheading:15767259-Enterotoxins, pubmed-meshheading:15767259-Enzyme Activation, pubmed-meshheading:15767259-Enzyme Inhibitors, pubmed-meshheading:15767259-Humans, pubmed-meshheading:15767259-Ileum, pubmed-meshheading:15767259-Imidazoles, pubmed-meshheading:15767259-Immunohistochemistry, pubmed-meshheading:15767259-Inflammation, pubmed-meshheading:15767259-Intramolecular Oxidoreductases, pubmed-meshheading:15767259-Luciferases, pubmed-meshheading:15767259-Membrane Proteins, pubmed-meshheading:15767259-Mice, pubmed-meshheading:15767259-Mice, SCID, pubmed-meshheading:15767259-Models, Biological, pubmed-meshheading:15767259-Nitrobenzenes, pubmed-meshheading:15767259-Phosphorylation, pubmed-meshheading:15767259-Prostaglandin-Endoperoxide Synthases, pubmed-meshheading:15767259-Protein Binding, pubmed-meshheading:15767259-Pyridines, pubmed-meshheading:15767259-RNA, pubmed-meshheading:15767259-RNA, Messenger, pubmed-meshheading:15767259-Reactive Oxygen Species, pubmed-meshheading:15767259-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:15767259-Signal Transduction, pubmed-meshheading:15767259-Sulfonamides, pubmed-meshheading:15767259-Time Factors, pubmed-meshheading:15767259-Tissue Transplantation, pubmed-meshheading:15767259-Transfection, pubmed-meshheading:15767259-p38 Mitogen-Activated Protein Kinases
pubmed:year
2005
pubmed:articleTitle
Clostridium difficile toxin A regulates inducible cyclooxygenase-2 and prostaglandin E2 synthesis in colonocytes via reactive oxygen species and activation of p38 MAPK.
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