title: 17β-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-γ/STAT1-dependent miR-7 upregulation.
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-γ (IFN-γ), significantly increased miR-7 transcriptional activity and resulted in upregulated miR-7 and loss of EGFR. Additionally, we demonstrated a role for the anti-inflammatory steroid, 17β-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 STAT1 expression 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.
authors.affiliation: Institute of Nephrology, Wales Kidney Research Unit, Division of Infection and Immunity, Cardiff University, College of Biomedical and Life Sciences, University Hospital of Wales, Heath Park, Wales, CF14 4XN, UK.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Midgley
authors.affiliation: Institute of Nephrology, Wales Kidney Research Unit, Division of Infection and Immunity, Cardiff University, College of Biomedical and Life Sciences, University Hospital of Wales, Heath Park, Wales, CF14 4XN, UK.
authors.forename: Glyn
authors.initials: G
authors.lastname: Morris
authors.affiliation: Institute of Nephrology, Wales Kidney Research Unit, Division of Infection and Immunity, Cardiff University, College of Biomedical and Life Sciences, University Hospital of Wales, Heath Park, Wales, CF14 4XN, UK.
authors.forename: Aled O
authors.initials: AO
authors.lastname: Phillips
authors.affiliation: Institute of Nephrology, Wales Kidney Research Unit, Division of Infection and Immunity, Cardiff University, College of Biomedical and Life Sciences, University Hospital of Wales, Heath Park, Wales, CF14 4XN, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Steadman
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D054443:Cell Migration Assays; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D003094:Collagen / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005782:Gels / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D003094:Collagen; D004958:Estradiol; D005782:Gels; D018836:Inflammation Mediators; D007371:Interferon-gamma; D035683:MicroRNAs; D011960:Receptors, Estrogen; D050794:STAT1 Transcription Factor; D053773:Transforming Growth Factor beta1; C549242:MIRN7-1 microRNA, human; C494079:STAT1 protein, human
keywords: 17β-estradiol; fibroblast; interferon-γ; microRNA-7; myofibroblast; wound healing