Microsomal prostaglandin E synthase-1 is overexpressed in inflammatory bowel disease. Evidence for involvement of the transcription factor Egr-1
| Autor: | Kotha, Subbaramaiah, Kazuhiko, Yoshimatsu, Ellen, Scherl, Kiron M, Das, Kenneth D, Glazier, Dragan, Golijanin, Robert A, Soslow, Tadashi, Tanabe, Hiroaki, Naraba, Andrew J, Dannenberg |
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| Rok vydání: | 2004 |
| Předmět: |
Indazoles
Transcription Genetic Colon Blotting Western Immunoblotting Enzyme Activators Nitric Oxide Transfection Models Biological Immediate-Early Proteins Cell Line Tumor Microsomes Humans Enzyme Inhibitors Intestinal Mucosa Withdrawals/Retractions Luciferases Promoter Regions Genetic Cells Cultured Protein Kinase C Early Growth Response Protein 1 Prostaglandin-E Synthases Inflammation Dose-Response Relationship Drug Tumor Necrosis Factor-alpha Oligonucleotides Antisense Blotting Northern Inflammatory Bowel Diseases Immunohistochemistry DNA-Binding Proteins Intramolecular Oxidoreductases Guanylate Cyclase Type C Phospholipases RNA Interference Plasmids Signal Transduction Transcription Factors |
| Zdroj: | The Journal of biological chemistry. 279(13) |
| ISSN: | 0021-9258 |
| Popis: | Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the conversion of cyclooxygenase-derived prostaglandin (PG) H(2) to PGE(2). Increased amounts of mPGES-1 were detected in inflamed intestinal mucosa from patients with inflammatory bowel disease (IBD). Treatment with tumor necrosis factor (TNF)-alpha stimulated mPGES-1 transcription in human colonocytes, resulting in increased amounts of mPGES-1 mRNA and protein. The inductive effect of TNF-alpha localized to the GC box region of the mPGES-1 promoter. Binding of Egr-1 to the GC box region of the mPGES-1 promoter was enhanced by treatment with TNF-alpha. Notably, increased Egr-1 expression and binding activity were also detected in inflamed mucosa from IBD patients. Treatment with TNF-alpha induced the activities of phosphatidylcholine-phospholipase C (PC-PLC) and protein kinase (PK) C and enhanced NO production. A pharmacological approach was used to implicate PC-PLC --PKC --NO signaling as being important for the induction of mPGES-1 by TNF-alpha. TNF-alpha also enhanced guanylate cyclase activity and inhibitors of guanylate cyclase activity blocked the induction of mPGES-1 by TNF-alpha. YC-1, an activator of guanylate cyclase, induced mPGES-1. Overexpressing a dominant negative form of PKG blocked TNF-alpha-mediated stimulation of the mPGES-1 promoter. Taken together, these results suggest that overexpression of mPGES-1 in IBD is the result of Egr-1-mediated activation of transcription. Moreover, TNF-alpha induced mPGES-1 by stimulating PC-PLC --PKC --NO --cGMP --PKG signal transduction pathway. |
| Databáze: | OpenAIRE |
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