Microsomal prostaglandin E synthase-1 is overexpressed in inflammatory bowel disease. Evidence for involvement of the transcription factor Egr-1.
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.
Subbaramaiah
Kotha
K
Department of Medicine, New York Presbyterian Hospital, Weill Medical College of Cornell University and Strang Cancer Prevention Center, 1300 York Avenue, Room F-203A, New York, NY 10021, USA. ksubba@med.cornell.edu
Yoshimatsu
Kazuhiko
K
Scherl
Ellen
E
Das
Kiron M
KM
Glazier
Kenneth D
KD
Golijanin
Dragan
D
Soslow
Robert A
RA
Tanabe
Tadashi
T
Naraba
Hiroaki
H
Dannenberg
Andrew J
AJ
D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003106:Colon / Q000166:cytology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins; D015151:Immunoblotting; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology; D007249:Inflammation; D015212:Inflammatory Bowel Diseases / Q000201:enzymology*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis*; D008156:Luciferases / Q000378:metabolism; D008861:Microsomes / Q000201:enzymology*; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000071876:Prostaglandin-E Synthases; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D007191:Indazoles; D016376:Oligonucleotides, Antisense; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D009569:Nitric Oxide; D008156:Luciferases; D011493:Protein Kinase C; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C; D006162:Guanylate Cyclase; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases