Microsomal prostaglandin E synthase-1 is overexpressed in inflammatory bowel disease: Evidence for involvement of the transcription factor Egr-1 Journal Article
| Authors: | Subbaramaiah, K.; Yoshimatsu, K.; Scherl, E.; Das, K. M.; Glazier, K. D.; Golijanin, D.; Soslow, R. A.; Tanabe, T.; Naraba, H.; Dannenberg, A. J. |
| Article Title: | Microsomal prostaglandin E synthase-1 is overexpressed in inflammatory bowel disease: Evidence for involvement of the transcription factor Egr-1 |
| Abstract: | Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the conversion of cyclooxygenase-derived prostaglandin (PG) H2 to PGE2. Increased amounts of mPGES-1 were detected in inflamed intestinal mucosa from patients with inflammatory bowel disease (IBD). Treatment with tumor necrosis factor (TNF)-α stimulated mPGES-1 transcription in human colonocytes, resulting in increased amounts of mPGES-1 mRNA and protein. The inductive effect of TNF-α 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-α. Notably, increased Egr-1 expression and binding activity were also detected in inflamed mucosa from IBD patients. Treatment with TNF-α 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-α TNF-α also enhanced guanylate cyclase activity and inhibitors of guanylate cyclase activity blocked the induction of mPGES-1 by TNF-α. YC-1, an activator of guanylate cyclase, induced mPGES-1. Overexpressing a dominant negative form of PKG blocked TNF-α-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-α induced mPGES-1 by stimulating PC-PLC → PKC → NO → cGMP → PKG signal transduction pathway. |
| Keywords: | immunohistochemistry; signal transduction; human cell; promoter region; dna-binding proteins; protein localization; cells, cultured; gene overexpression; models, biological; inflammation; rna interference; transcription, genetic; dose-response relationship, drug; enzyme activity; cell line, tumor; transfection; transcription factors; blotting, western; tumor necrosis factor alpha; tumor necrosis factor-alpha; tumors; enzyme inhibitors; immunoblotting; enteritis; plasmids; protein kinase c; inflammatory bowel diseases; catalysis; drug therapy; luciferases; prostaglandin e; biochemistry; blotting, northern; immediate-early proteins; colon; diseases; phosphatidylcholine; pleiotropy; hormones; enzyme induction; oligonucleotides, antisense; intestine mucosa; nitric oxide; intramolecular oxidoreductases; indazoles; intestinal mucosa; promoter regions (genetics); early growth response protein 1; prostaglandin synthase; guanylate cyclase; microsomes; phospholipase c; humans; human; priority journal; article; tumor necrosis factors (tnf); prostaglandin h2; transcription factor egr 1; microsome membrane; enzyme activators |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 279 |
| Issue: | 13 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2004-03-26 |
| Start Page: | 12647 |
| End Page: | 12658 |
| Language: | English |
| DOI: | 10.1074/jbc.M312972200 |
| PROVIDER: | scopus |
| PUBMED: | 14722058 |
| DOI/URL: | |
| Notes: | J. Biol. Chem. -- Cited By (since 1996):87 -- Export Date: 16 June 2014 -- CODEN: JBCHA -- Source: Scopus |
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