Background/Purpose: Systemic Sclerosis (SSc) is a disease characterized by an increase in the synthesis of extracellular matrix (ECM) components in various organs, including the skin, resulting in increased morbidity. Like most autoimmune diseases, SSc has a female predominance that increases during childbearing years. Interestingly, post-menopausal SSc patients have higher circulating estradiol (E2) levels compared to age-matched controls. E2 exerts pro-fibrotic and pro-inflammatory activity, increasing ECM components and IL-6, both of which are also increased in SSc patients. Aromatase (CYP19) is a cytochrome p450 enzyme active in extra-gonadal tissues, including the skin. It is responsible for the aromatization of androgens into estrogens. Increased activity of aromatase may underlie the increase E2 levels in SSc patients. Since SSc dermal fibroblasts secrete increased levels of IL-6, and increased E2 levels are reported in SSc patients, we hypothesized that there is an interplay between E2 and IL-6 contributing to the pro-fibrotic phenotype.

Methods: Human skin in organ culture was stimulated with E2 or IL-6 and its soluble receptor, sIL6R, for 24 or 48 hours. Transcript levels of aromatase, IL-6, and collagen 1A1 were measured using real-time PCR. Aromatase activity was measured using an ELISA-based testosterone conversion assay. Statistical significance was determined using ANOVA, with significance defined as p≤0.05.

Results: Human skin stimulated with E2 or IL-6 + sIL-6R ex vivo showed increased levels of collagen. E2 stimulation also resulted in increased IL-6 transcript and protein levels. Stimulation of human skin with IL-6 and sIL-6R led to increases in the levels of aromatase mRNA. Skin samples stimulated with IL-6 and sIL-6R also had increased aromatase activity, translating into increased conversion of testosterone into estradiol. The aromatase activity decreased significantly after treatment with anastrozole, an aromatase inhibitor.

Conclusion: Our data show that both E2 and IL-6 exert pro-fibrotic effects in human skin. Our findings further establish the existence of a positive feedback loop between E2 and IL-6, supporting a pro-fibrotic cycle that leads to increased ECM production and fibrosis. Our results implicate E2 and IL-6 in dermal fibrosis in SSc. Our results also suggest that effective therapies for SSc may require concomitant inhibition of E2 and IL-6.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-positive-feedback-loop-between-estrogen-and-il-6-leads-to-fibrosis-in-human-skin/