Interaction of estrogen and interleukin 6 in the progression of lymphangioleiomyomatosis

Abstract

Lymphangioleiomyomatosis (LAM) is an estrogen-dependent disease that promotes tumor cell growth through estrogen receptor α (ERα). Interleukin 6 (IL-6) is an important estrogen (E2) target gene; however, its role in disease progression remains unclear. In the present study, we investigated the biological functions and underlying mechanisms of action of IL-6 in E2-stimulated tuberous sclerosis complex 2 (TSC2)–deficient cells. The IL-6 levels in the lung tissue and serum of the patients were detected using immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). The effects of E2 and recombinant IL-6 on ERα and IL-6 signaling and the malignant behaviors of TSC2-deficient cells were examined using western blotting, immunofluorescence, Cell Counting Kit-8 (CCK-8), colony formation, transwell, and wound healing assays. The IL-6 expression was higher in LAM lung tissues than in controls, was significantly elevated in the serum of patients with LAM, and was negatively correlated with lung function. After E2 and recombinant human IL-6 (rhIL-6) intervention in TSC2-deficient cells, the expression of IL-6 and ERα was upregulated in a time-dependent manner. Fulvestrant treatment had no significant inhibitory effect on IL-6 protein expression, whereas Stattic intervention inhibited ERα expression. The combined use of fulvestrant and Stattic significantly suppressed the proliferation and migration of TSC2-deficient cells, indicating that the IL-6/signal transducer and activator of transcription 3 (STAT3) pathway plays an important role in E2-promoted LAM progression and may serve as a potential therapeutic target for LAM.