Microsomal prostaglandin E synthase-1 is overexpressed in inflammatory bowel disease: Evidence for involvement of the transcription factor Egr-1

Kotha Subbaramaiah, Kazuhiko Yoshimatsu, Ellen Scherl, Kiron M. Das, Kenneth D. Glazier, Dragan Golijanin, Robert A. Soslow, Tadashi Tanabe, Hiroaki Naraba, Andrew J. Dannenberg

Research output: Contribution to journalArticle

111 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)12647-12658
Number of pages12
JournalJournal of Biological Chemistry
Volume279
Issue number13
DOIs
StatePublished - Mar 26 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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