TLR4-associated IRF-7 and NFĸB signaling acts as a molecular link between androgen and metformin activities and cytokine synthesis in the PCOS endometrium.

• 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.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.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 anti-androgen. Although 17β-estradiol (E2) decreased p-IRF-7 expression with little effect on TLR-mediated IRF7 and NFκB signaling or on cytokine protein levels, exposure to metformin alone or in combination with E2 suppressed IRAK4, p-IRF-7, IRF-7, IKKα, p-NFκB p65, IFNɣ, and TNFα protein expression.Cytokine synthesis and increased endometrial inflammation in PCOS patients is coupled to androgen-induced TLR4/IRF-7/NFkB signaling, which is be inhibited by metformin treatment.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Reproduktionsmedicin och gynekologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Obstetrics, Gynaecology and Reproductive Medicine (hsv//eng)

Nyckelord

androgen

TLR4/IRF7/NFκB

innate immune response

endometrial inflammation

polycystic ovary syndrome

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