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TLR4-associated IRF...
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Hu, MinGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology
(author)
TLR4-associated IRF-7 and NFĸB signaling acts as a molecular link between androgen and metformin activities and cytokine synthesis in the PCOS endometrium.
- Article/chapterEnglish2021
Publisher, publication year, extent ...
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2020-12-31
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The Endocrine Society,2021
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LIBRIS-ID:oai:gup.ub.gu.se/300129
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https://gup.ub.gu.se/publication/300129URI
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https://doi.org/10.1210/clinem/dgaa951DOI
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Subject category:art swepub-publicationtype
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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.
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Zhang, YuehuiGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology
(author)
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Li, Xin,1985Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology(Swepub:gu)xilia
(author)
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Cui, PengGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology(Swepub:gu)xcuipe
(author)
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Sferruzzi-Perri, Amanda Nancy
(author)
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Brännström, Mats,1958Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institutionen för kliniska vetenskaper, Avdelningen för obstetrik och gynekologi,Institute of Clinical Sciences, Department of Surgery,Institute of Clinical Sciences, Department of Obstetrics and Gynecology(Swepub:gu)xbrmat
(author)
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Shao, Linus Ruijin,1964Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology(Swepub:gu)xsharu
(author)
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Billig, Håkan,1955Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology,Institute of Neuroscience and Physiology, Department of Physiology(Swepub:gu)xbilha
(author)
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Göteborgs universitetInstitutionen för neurovetenskap och fysiologi, sektionen för fysiologi
(creator_code:org_t)
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In:The Journal of clinical endocrinology and metabolism: The Endocrine Society106:4, s. 1022-10401945-71970021-972X
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Zhang, Yuehui
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