Estradiol suppresses NF-kappa B activation through coordinated regulation of let-7a and miR-125b in primary human macrophages.
Previous findings suggest that 17beta-estradiol (estradiol) has a suppressive effect on TNF-alpha, but the mechanism by which estradiol regulates TNF-alpha expression in primary human macrophages is unknown. In this article, we demonstrate that pretreatment of human macrophages with estradiol attenuates LPS-induced TNF-alpha expression through the suppression of NF-kappaB activation. Furthermore, we show that activation of macrophages with LPS decreases the expression of kappaB-Ras2, an inhibitor of NF-kappaB signaling. Estradiol pretreatment abrogates this decrease, leading to the enhanced expression of kappaB-Ras2 with LPS stimulation. Additionally, we identified two microRNAs, let-7a and miR-125b, which target the kappaB-Ras2 3' untranslated region (UTR). LPS induces let-7a and inhibits miR-125b expression in human macrophages, and pretreatment with estradiol abrogates these effects. 3'UTR reporter assays demonstrate that let-7a destabilizes the kappaB-Ras2 3'UTR, whereas miR-125b enhances its stability, resulting in decreased kappaB-Ras2 in response to LPS. Our data suggest that pretreatment with estradiol reverses this effect. We propose a novel mechanism for estradiol inhibition of LPS-induced NF-kappaB signaling in which kappaB-Ras2 expression is induced by estradiol via regulation of let-7a and miR-125b. These findings are significant in that they are the first to demonstrate that estradiol represses NF-kappaB activation through the induction of kappaB-Ras2, a key inhibitor of NF-kappaB signaling.
Murphy
Amy J
AJ
Department of Physiology, Dartmouth Medical School, Lebanon, NH 03756, USA.
Guyre
Paul M
PM
Pioli
Patricia A
PA
D020413:3' Untranslated Regions / Q000276:immunology; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology*; D004958:Estradiol / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D020298:U937 Cells; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D020413:3' Untranslated Regions; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C487931:mirnlet7 microRNA, human; D004958:Estradiol; D018631:ras Proteins