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Estradiol suppresses NF-kappa B activation through coordinated regulation of let-7a and miR-125b in primary human macrophages.
J Immunol. 2010 May 01; 184(9):5029-37.JI

Abstract

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.

Authors+Show Affiliations

Department of Physiology, Dartmouth Medical School, Lebanon, NH 03756, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20351193

Citation

Murphy, Amy J., et al. "Estradiol Suppresses NF-kappa B Activation Through Coordinated Regulation of Let-7a and miR-125b in Primary Human Macrophages." Journal of Immunology (Baltimore, Md. : 1950), vol. 184, no. 9, 2010, pp. 5029-37.
Murphy AJ, Guyre PM, Pioli PA. Estradiol suppresses NF-kappa B activation through coordinated regulation of let-7a and miR-125b in primary human macrophages. J Immunol. 2010;184(9):5029-37.
Murphy, A. J., Guyre, P. M., & Pioli, P. A. (2010). Estradiol suppresses NF-kappa B activation through coordinated regulation of let-7a and miR-125b in primary human macrophages. Journal of Immunology (Baltimore, Md. : 1950), 184(9), 5029-37. https://doi.org/10.4049/jimmunol.0903463
Murphy AJ, Guyre PM, Pioli PA. Estradiol Suppresses NF-kappa B Activation Through Coordinated Regulation of Let-7a and miR-125b in Primary Human Macrophages. J Immunol. 2010 May 1;184(9):5029-37. PubMed PMID: 20351193.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Estradiol suppresses NF-kappa B activation through coordinated regulation of let-7a and miR-125b in primary human macrophages. AU - Murphy,Amy J, AU - Guyre,Paul M, AU - Pioli,Patricia A, Y1 - 2010/03/29/ PY - 2010/3/31/entrez PY - 2010/3/31/pubmed PY - 2010/7/2/medline SP - 5029 EP - 37 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J. Immunol. VL - 184 IS - 9 N2 - 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. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/20351193/full_citation L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=20351193 DB - PRIME DP - Unbound Medicine ER -