TLR4-associated IRF-7 and NFĸB signaling acts as a molecular link between androgen and metformin activities and cytokine synthesis in the PCOS endometrium
Abstract
BACKGROUND
Low-grade chronic inflammation is commonly seen in polycystic ovary syndrome (PCOS) patients with elevated levels of inflammatory cytokines in the endometrium. However, our understanding of the mechanisms underlying cytokine synthesis and increased endometrial inflammation in PCOS patients remains limited.
METHODS
Endometrial biopsy samples were collected from non-PCOS (n = 17) and PCOS (n = 22) patients either during the proliferative phase of the menstrual cycle or with hyperplasia. Endometrial explants were prepared from PCOS patients and subjected to pharmacological manipulation in vitro. The expression and localization of TLR2/4, key elements of innate immune signal transduction and NFκB signaling pathways, and multiple cytokines were comprehensively evaluated by Western blotting, immunohistochemistry, and immunofluorescence in endometrial tissues.
RESULTS
We demonstrated the distribution of protein expression and localization associated with the significantly increased androgen receptor, TLR2, and TLR4-mediated activation of IRF-7 and NFkB signaling, cytokine production, and endometrial inflammation in PCOS patients compared to non-PCOS patients with and without endometrial hyperplasia. In vitro experiments showed that 5α-dihydrotestosterone (DHT) enhanced androgen receptor, TLR4, IRF-7, and p-NFκB p65 protein expression along with increased IFNα and IFNɣ abundance. The effects of DHT on IRF-7, p-NFκB p65, and IFN abundance were abolished by flutamide, an…
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