{"entity": "publication", "iuid": "adc9079acc3040a69b2eba909277584d", "timestamp": "2026-08-09T04:16:46.554Z", "links": {"self": {"href": "https://publications.scilifelab.se/publication/adc9079acc3040a69b2eba909277584d.json"}, "display": {"href": "https://publications.scilifelab.se/publication/adc9079acc3040a69b2eba909277584d"}}, "title": "TLR4-Associated IRF-7 and NF\u03baB Signaling Act as a Molecular Link Between Androgen and Metformin Activities and Cytokine Synthesis in the PCOS Endometrium.", "authors": [{"family": "Hu", "given": "Min", "initials": "M"}, {"family": "Zhang", "given": "Yuehui", "initials": "Y"}, {"family": "Li", "given": "Xin", "initials": "X"}, {"family": "Cui", "given": "Peng", "initials": "P"}, {"family": "Sferruzzi-Perri", "given": "Amanda Nancy", "initials": "AN"}, {"family": "Br\u00e4nnstr\u00f6m", "given": "Mats", "initials": "M"}, {"family": "Shao", "given": "Linus R", "initials": "LR"}, {"family": "Billig", "given": "H\u00e5kan", "initials": "H"}], "type": "journal article", "published": "2021-03-25", "journal": {"title": "J. Clin. Endocrinol. Metab.", "issn": "1945-7197", "volume": "106", "issue": "4", "pages": "1022-1040", "issn-l": "0021-972X"}, "abstract": "Low-grade chronic inflammation is commonly seen in polycystic ovary syndrome (PCOS) patients with elevated levels of inflammatory cytokines in the endometrium.\n\nThis work aimed to increase the limited understanding of the mechanisms underlying cytokine synthesis and increased endometrial inflammation in PCOS patients.\n\nEndometrial 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 underwent pharmacological manipulation in vitro. The expression and localization of toll-like receptor 2 (TLR2)/4, key elements of innate immune signal transduction and nuclear factor \u03baB (NF\u03baB) signaling pathways, and multiple cytokines were comprehensively evaluated by Western blotting, immunohistochemistry, and immunofluorescence in endometrial tissues.\n\nWe demonstrated the distribution of protein expression and localization associated with the significantly increased androgen receptor, TLR2, and TLR4-mediated activation of interferon regulatory factor-7 (IRF-7) and NF\u03baB signaling, cytokine production, and endometrial inflammation in PCOS patients compared to non-PCOS patients with and without endometrial hyperplasia. In vitro experiments showed that 5-dihydrotestosterone (DHT) enhanced androgen receptor, TLR4, IRF-7, and p-NF\u03baB p65 protein expression along with increased interferon \u03b1 (IFN\u03b1) and IFN\u0263 abundance. The effects of DHT on IRF-7, p-NF\u03baB p65, and IFN abundance were abolished by flutamide, an antiandrogen. Although 17\u03b2-estradiol (E2) decreased p-IRF-7 expression with little effect on TLR-mediated IRF7 and NF\u03baB signaling or on cytokine protein levels, exposure to metformin alone or in combination with E2 suppressed interleukin-1 receptor-associated kinase 4 (IRAK4), p-IRF-7, IRF-7, I\u03baB kinase \u03b1 (IKK\u03b1), p-NF\u03baB p65, IFN\u0263, and tumor necrosis factor \u03b1 protein expression.\n\nCytokine synthesis and increased endometrial inflammation in PCOS patients are coupled to androgen-induced TLR4/IRF-7/NF\u03baB signaling, which is inhibited by metformin treatment.", "doi": "10.1210/clinem/dgaa951", "pmid": "33382900", "labels": {"Integrated Microscopy Technologies Gothenburg": "Service"}, "xrefs": [{"db": "pii", "key": "6056640"}], "notes": [], "created": "2023-02-16T08:16:53.960Z", "modified": "2023-02-16T08:16:53.974Z"}