A Positive Feedback Loop Exists between Estradiol and IL-6 and Contributes to Dermal Fibrosis.

Area of Science:

• Dermatology
• Endocrinology
• Immunology

Background:

• Systemic sclerosis (SSc) involves dermal fibrosis and shows a female predominance, suggesting hormonal involvement.
• Elevated interleukin-6 (IL-6) in SSc patients and high estradiol (E2) in post-menopausal women suggest a hormonal link.
• IL-6 in skin increases aromatase activity, converting testosterone to E2, potentially linking IL-6 and E2 in fibrosis.

Purpose of the Study:

• To investigate the interplay between estradiol (E2) and interleukin-6 (IL-6) in contributing to dermal fibrosis in systemic sclerosis (SSc).
• To determine if IL-6 influences E2 production and vice versa in human dermal fibroblasts and skin tissues.

Main Methods:

• Primary dermal fibroblasts and skin tissues from healthy donors and SSc patients were used.
• Tissues and cells were stimulated with IL-6/sIL-6R or E2, and treated with aromatase inhibitor (anastrozole) or estrogen receptor inhibitor (fulvestrant).
• Levels of fibronectin (FN), type III collagen A1 (Col IIIA1), and type V collagen A1 (Col VA1) were measured.

Main Results:

• IL-6+sIL-6R stimulation induced E2 production in healthy dermal fibroblasts and tissues.
• E2 stimulation induced IL-6 production in dermal tissues and fibroblasts.
• Inhibition of aromatase or estrogen receptor significantly reduced fibronectin and collagen production in SSc fibroblasts and IL-6-stimulated cells.

Conclusions:

• Interleukin-6 (IL-6) contributes to dermal fibrosis in systemic sclerosis (SSc) partly through estradiol (E2).
• A positive feedback loop exists between E2 and IL-6 in human skin, promoting fibrotic processes.
• Targeting this IL-6/E2 axis may offer therapeutic strategies for SSc dermal fibrosis.