Suppression of tumor necrosis factor (TNF-alpha) gene expression by prostaglandin E(2). Role Of early growth response protein-1 (Egr-1).
We examined the mechanism by which PGE(2)suppresses the expression of TNF-alpha in human macrophages and synovial fibroblasts. Prostaglandin E(2)increased, in a time and dose-dependent (EC(50)75+/-15ng/ml, mean+/-SD) fashion, the expression and synthesis of Egr-1/Krox24 as judged by Northern blotting and electrophoretic mobility gel-shift analysis, respectively. In human macrophagic THP-1 cells, rhIL-17 increased promoter activity by 7. 6+/-0.35-fold over controls, an effect that was abrogated in a dose-dependent fashion by coincubations with PGE(2)(IC(50)25+/-4ng/ml). An intact Egr-1/Krox-24 enhancer sequence in the TNF-alpha promoter region was essential for the latter PGE(2)-dependent inhibitory effect as double base substitutions (GC-->TT) in the sequence curtailed promoter response to PGE(2). Overexpression of two dominant negative Egr-1/Krox-24 constructs in THP-1 cells considerably diminished the inhibitory effects of PGE(2)on rhIL-17-induced TNF-alpha mRNA expression. We conclude that PGE(2)inhibits induced TNF-alpha expression in target cells through an Egr-1/Krox-24 mediated signaling process.
Di Battista
J A
JA
University of Montreal, Montréal, Canada.
Martel-Pelletier
J
J
Pelletier
J
J
D015152:Blotting, Northern; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D015232:Dinoprostone / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1; D015870:Gene Expression; D006801:Humans; D017874:Immediate-Early Proteins; D020381:Interleukin-17 / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D020381:Interleukin-17; D012333:RNA, Messenger; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D015232:Dinoprostone