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17{beta}-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-{gamma}/STAT1-dependent miR-7 upregulation

Midgley, Adam Christopher, Morris, Nathanael Glyn, Phillips, Aled Owain and Steadman, Robert 2016. 17{beta}-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-{gamma}/STAT1-dependent miR-7 upregulation. Aging Cell 15 (3) , pp. 531-541. 10.1111/acel.12462

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Abstract

Age-related defects in fibroblast differentiation and functionality were previously shown to be associated with impaired hyaluronan (HA) synthase 2 (HAS2) and epidermal growth factor receptor (EGFR) function, as a result of upregulated microRNA-7 (miR-7) expression. In aging fibroblasts, inhibiting miR-7 prevented the dysregulation of the HA-mediated CD44/EGFR signaling pathway. Here, we investigated transcriptional upregulation of miR-7 and implicated the age-associated over-activation of JAK/STAT1 as a primary candidate. STAT1 binding sites were identified on the putative miR-7 promoter and stimulation of fibroblasts with the inflammatory cytokine, interferon-{gamma} (IFN-{gamma}), significantly increased miR-7 transcriptional activity and resulted in upregulated miR-7 and loss of EGFR. Additionally, we demonstrated arole for the anti-inflammatory steroid, 17b-estradiol (E2), in the attenuation of miR-7 expression. E2 stimulation promoted estrogen receptor (ER) interactions with the miR-7 putative promoter and suppressed miR-7 expression. E2 also attenuated STAT1expression and activity. Furthermore, treatments with E2 restored fibroblast functionality, including proliferation, migration and differentiation, key events in effective wound healing. In light of our findings, we propose that the regulation of miR-7 by pro- and anti-inflammatory mediators plays a wider role than previously thought. The modulation of fibroblast functions and ultimately wound healing by miR-7 activators or inhibitors could provide realistic targets for the restoration of chronic wound healing capabilities in the elderly.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Wiley-Blackwell
ISSN: 1474-9718
Related URLs:
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 10 February 2016
Last Modified: 22 Jun 2019 22:07
URI: http://orca-mwe.cf.ac.uk/id/eprint/87501

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