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toll like receptor 3 OKDB#: 2191
 Symbols: TLR3 Species: human
 Synonyms: CD283, IIAE2  Locus: 4q35.1 in Homo sapiens
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For retrieval of Nucleotide and Amino Acid sequences please go to: OMIM Entrez Gene
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General Comment This gene was found in a mouse DNA array analysis of transcripts expressed in mouse preovulatory follicles.

NCBI Summary: The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta and pancreas, and is restricted to the dendritic subpopulation of the leukocytes. It recognizes dsRNA associated with viral infection, and induces the activation of NF-kappaB and the production of type I interferons. It may thus play a role in host defense against viruses. Use of alternative polyadenylation sites to generate different length transcripts has been noted for this gene. [provided by RefSeq, Jul 2008]
General function Receptor
Comment
Cellular localization Plasma membrane
Comment
Ovarian function Follicle atresia, Steroid metabolism
Comment Poly (I:C) induces innate immune responses via Toll-like receptor 3 in human ovarian granulosa cells. Yan K et al. (2019) The ovary can be infected by a variety of viruses, which may come from the female reproductive tract (FRT) or the peritoneum. The innate immune responses to viral infection in the human ovary are poorly understood. The present study demonstrated that human ovarian granulosa cells had innate immune activity in response to viral RNA challenge through Toll-like receptor 3 (TLR3) activation. TLR3 was constitutively expressed in the human ovary and predominantly located in granulosa cells of developmental follicles at all stages. Polyinosinic-polycytidylic acid poly (I:C)], a synthetic viral double-stranded RNA analogue, induced innate immune responses in human ovarian granulosa cells and affected endocrine function. Poly (I:C) significantly up-regulated pro-inflammatory cytokines, including TNF-α, IL-6, IL-1β, and type I interferons (IFN-α/β), and the innate immune responses were significantly reduced by blocking TLR3 signaling. Furthermore, poly (I:C) induced antiviral genes expression, including 2'-5'-oligoadenylate synthetase, Mx GTPase 1, IFN-stimulating gene 15, and dsRNA-activated protein kinase R. In contrast, the expression of P450 aromatase and inhibin was dramatically inhibited by poly (I:C). Both silencing of TLR3 and neutralizing TNF-α reversed the inhibitory effect of poly (I:C) on P450 aromatase and inhibin expression. Our study demonstrates that granulosa cells play a potential role in innate immune protection against viral infection in the normal human ovary, and the innate immune response perturbs cell endocrine function. This article is protected by copyright. All rights reserved.////////////////// Polyinosinic-Polycytidylic Acid Perturbs Ovarian Functions Through Toll-Like Receptor 3-Mediated Tumor Necrosis Factor A Production in Female Mice. [Yan K et al. (2015) Viral infections may perturb ovarian functions and female fertility. Mechanisms underlying viral perturbation of ovarian functions are incompletely understood. This study found that intraperitoneal injection of polyinosinic-polycytidylic acid poly(I:C)] in female mice inhibits estradiol synthesis and induces ovarian granulosa cell apoptosis. Poly(I:C) is a synthetic viral double-stranded RNA analog, which induces innate antiviral responses mimicking a viral infection through activation of pattern recognition receptors, including Toll-like receptor 3 (TLR3), retinoic acid-inducible gene I, and melanoma differentiation-associated gene 5. Poly(I:C) injection significantly induced granulosa cell apoptosis in antral follicles and reduced antral follicle numbers. These effects were significantly diminished in Tlr3 knockout or tumor necrosis factor-alpha (Tnfa) knockout mice. We demonstrated that poly(I:C) injection induced TNFA production at relatively high level in wild-type mice compared with Tlr3 knockout mice. Notably, TNFA neutralizing antibody significantly reduced poly(I:C)-induced ovarian dysfunction. In vitro assays confirmed that TNFA inhibits estradiol synthesis and induces granulosa cell apoptosis. Results provide novel insights into the mechanisms by which a mimic viral infection perturbs ovarian functions in mice.////////////////// Polyinosinic-Polycytidylic Acid Initiates Ovarian Innate Antiviral Response and Inhibits Steroidogenesis in Female Mice. [Yan K 2013 et al. Viral infection may perturb ovarian functions. However, innate antiviral response in the ovary has not been intensively investigated. In this study, we examined the innate antiviral system in the mouse ovary and the impacts of antiviral response on steroidogenesis. Major virus sensors, including Toll-like receptor 3 (TLR3), retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5), are predominantly expressed in ovarian stromal and granulosa cells. Polyinosinic-polycytidylic acid [poly(I:C)] is a common agonist of TLR3, MDA5, and RIG-I. Intraperitoneal injection of poly(I:C) activated nuclear factor kappa B and interferon (IFN) regulatory factor 3 in the ovarian cells, and induced the expression of pro-inflammatory cytokines, including tumor necrosis factor alpha, interleukin 6, and type 1 interferons (IFNA/B). Moreover, poly(I:C) upregulated the expression of several antiviral proteins, including 2'-5'-oligoadenylate synthetase, IFN-stimulated gene 15, and Mx GTPase 1. The innate antiviral response in the ovary was significantly reduced in Tlr3-deficient mice. Notably, we demonstrated that poly(I:C) injection inhibits steroidogenesis enzyme expression and decreases plasma estradiol and testosterone levels. Results show that the mouse ovary is equipped with innate antiviral state, and the antiviral response perturbs ovarian endocrine function. /////////////////////////
Expression regulated by
Comment
Ovarian localization Oocyte, Granulosa
Comment Distinct expression patterns of TLR transcripts in human oocytes and granulosa cells from primordial and primary follicles. Ernst EH et al. (2020) Ovulation has long been regarded as a process resembling an inflammatory response. Previously, luteinizing hormone (LH) was shown to induce Toll-like receptor 2 (TLR2) and TLR4 in granulosa cells from preovulatory hormone-dependent follicles. However, whether this could already initiate before the hormone-dependent phase is currently unknown. The aim of this study was to investigate TLR genes in human oocytes and granulosa cells from primordial and primary ovarian follicles during the hormone-independent phase. A class-comparison study of existing oocyte and granulosa cell RNA sequencing transcriptomes from primordial (n = 539 follicles) and primary (n = 261) follicles collected from three patients was examined. This revealed a distinct expression pattern of TLR3, TLR4 and TLR5 transcripts. Interestingly, the TLR3 protein was differentially detected in both the oocyte and the granulosa cells in primordial and primary follicles, suggesting that TLR3 is maternally contributed both as mRNA and protein. Intracellularly, the compartmentalized TLR3 dot-like staining in the intersection between the oocyte and the surrounding primordial granulosa cells. The TLR4 protein was detected in both primordial and primary follicles, with a notable staining in the granulosa cells. We functionally challenged ovaries in vitro, by polyinosinic:polycytidylic acid (poly I:C) and LPS, known to activate TLR3 and TLR4, respectively, and found a tendency for increased IL-6 production, which was particular evident in the LPS-treated group. Based on the expression of TLRs, it is notably that human primordial and primary follicles express genes that would allow them to respond to innate immune proteins and cytokines during follicle activation.//////////////////Toll-like receptor 3 and RIG-I-like receptor activation induces innate antiviral responses in mouse ovarian granulosa cells. Yan K et al. Viral infections of the ovary can cause pathological conditions. However, innate antiviral responses in the ovary are poorly understood. In this study, we demonstrate that Toll-like receptor 3 (TLR3), retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are constitutively expressed in the mouse ovary and predominantly located in granulosa cells. Polyinosinic-polycytidylic acid [poly(I:C)], a common agonist of TLR3, MDA5 and RIG-I, induced innate antiviral responses in ovarian granulosa cells. Poly(I:C) up-regulated pro-inflammatory cytokines, including TNF-a and IL-6, and type I interferons (IFN-a/?. Moreover, poly(I:C) induced the expression of antiviral proteins, including 2'-5'-oligoadenylate synthetase, Mx GTPase 1 and IFN-stimulating gene 15, in granulosa cells. In contrast, P450 aromatase expression was inhibited by poly(I:C). The poly(I:C)-induced antiviral responses in TLR3 knockout (TLR3(-/-)) ovarian granulosa cells were reduced, and completely abolished by blocking of MDA5/RIG-I signaling. Further, the poly(I:C)-induced cytokine expression in TLR3(-/-) cells was reduced by knockdown of MDA5 or RIG-I. Data suggest that TLR3, MDA5 and RIG-I cooperate in mediating innate antiviral responses in granulosa cells, which may contribute to the defense of the ovary against viral infections.
Follicle stages
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created: Oct. 14, 2003, 11:39 a.m. by: xin   email:
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last update: June 2, 2020, 12:44 p.m. by: hsueh    email:



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