{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:29:59Z","timestamp":1792801799917,"version":"4.5.0"},"reference-count":59,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2024,6,30]],"date-time":"2024-06-30T00:00:00Z","timestamp":1719705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Scleroderma Foundation New Investigator Award","award":["T32AR050958"],"award-info":[{"award-number":["T32AR050958"]}]},{"name":"National Scleroderma Foundation New Investigator Award","award":["K24AR060297"],"award-info":[{"award-number":["K24AR060297"]}]},{"name":"National Scleroderma Foundation New Investigator Award","award":["K08AR078372"],"award-info":[{"award-number":["K08AR078372"]}]},{"name":"National Scleroderma Foundation New Investigator Award","award":["KL2TR001452"],"award-info":[{"award-number":["KL2TR001452"]}]},{"name":"National Scleroderma Foundation New Investigator Award","award":["UL1TR001450"],"award-info":[{"award-number":["UL1TR001450"]}]},{"name":"National Scleroderma Foundation New Investigator Award","award":["P30AR072582"],"award-info":[{"award-number":["P30AR072582"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Systemic sclerosis (SSc) is characterized by dermal fibrosis with a female predominance, suggesting a hormonal influence. Patients with SSc have elevated interleukin (IL)-6 levels, and post-menopausal women and older men also have high estradiol (E2) levels. In the skin, IL-6 increases the enzymatic activity of aromatase, thereby amplifying the conversion of testosterone to E2. Therefore, we hypothesized that an interplay between E2 and IL-6 contributes to dermal fibrosis. We used primary dermal fibroblasts from healthy donors and patients with diffuse cutaneous (dc)SSc, and healthy donor skin tissues stimulated with recombinant IL-6 and its soluble receptor (sIL-6R) or E2. Primary human dermal fibroblasts and tissues from healthy donors stimulated with IL-6+sIL-6R produced E2, while E2-stimulated dermal tissues and fibroblasts produced IL-6. Primary dermal fibroblasts from healthy donors treated with IL-6+sIL-6R and the aromatase inhibitor anastrozole (ANA) and dcSSc fibroblasts treated with ANA produced less fibronectin (FN), type III collagen A1 (Col IIIA1), and type V collagen A1 (Col VA1). Finally, dcSSc dermal fibroblasts treated with the estrogen receptor inhibitor fulvestrant also generated less FN, Col IIIA1, and Col VA1. Our data show that IL-6 exerts its pro-fibrotic influence in human skin in part through E2 and establish a positive feedback loop between E2 and IL-6.<\/jats:p>","DOI":"10.3390\/ijms25137227","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T12:58:42Z","timestamp":1719925122000},"page":"7227","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A Positive Feedback Loop Exists between Estradiol and IL-6 and Contributes to Dermal Fibrosis"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9224-1391","authenticated-orcid":false,"given":"DeAnna","family":"Baker Frost","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 822, MSC 637, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisa","family":"Savchenko","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine, Rocky Vista University, 4130 Rocky Vista Way, Billings, MT 59106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko","family":"Takamura","sequence":"additional","affiliation":[{"name":"Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7124-5158","authenticated-orcid":false,"given":"Bethany","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department of Public Health Sciences, Medical University of South Carolina, 135 Cannon Street, Room 305F, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roselyn","family":"Fierkens","sequence":"additional","affiliation":[{"name":"Barabara Davis Center, Department of Pediatrics, University of Colorado, School of Medicine, M20-3201N, 1775 Aurora Court, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"King","sequence":"additional","affiliation":[{"name":"School of Medicine, Morehouse College, 720 Westview Drive, Atlanta, GA 30310, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6750-6407","authenticated-orcid":false,"given":"Carol","family":"Feghali-Bostwick","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 822, MSC 637, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1136\/ard.50.Suppl_4.854","article-title":"Clinical Aspects of Systemic Sclerosis (Scleroderma)","volume":"50","author":"Silver","year":"1991","journal-title":"Ann. 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