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.
College of Osteopathic Medicine, Rocky Vista University, 4130 Rocky Vista Way, Billings, MT 59106, USA.
Int J Mol Sci. 2024 Jun 30;25(13):7227. doi: 10.3390/ijms25137227.
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.
系统性硬化症（SSc）的特征是皮肤纤维化，女性患病率较高，表明存在激素影响。SSc 患者的白细胞介素（IL）-6 水平升高，绝经后妇女和老年男性的雌二醇（E2）水平也较高。在皮肤中，IL-6 增加芳香酶的酶活性，从而放大睾酮向 E2 的转化。因此，我们假设 E2 和 IL-6 之间的相互作用导致皮肤纤维化。我们使用来自健康供体和弥漫性皮肤 SSc（dcSSc）患者的原代真皮成纤维细胞，以及用重组 IL-6 和其可溶性受体（sIL-6R）或 E2 刺激的健康供体皮肤组织。来自健康供体的原代真皮成纤维细胞和组织在受到 IL-6+sIL-6R 刺激后产生 E2，而 E2 刺激的真皮组织和成纤维细胞产生 IL-6。用 IL-6+sIL-6R 和芳香酶抑制剂阿那曲唑（ANA）处理的健康供体真皮成纤维细胞以及用 ANA 处理的 dcSSc 成纤维细胞产生的纤连蛋白（FN）、III 型胶原 A1（Col IIIA1）和 V 型胶原 A1（Col VA1）较少。最后，用雌激素受体抑制剂氟维司群处理的 dcSSc 真皮成纤维细胞也产生较少的 FN、Col IIIA1 和 Col VA1。我们的数据表明，IL-6 通过 E2 在人体皮肤中发挥其促纤维化作用，并在 E2 和 IL-6 之间建立了正反馈环。
