This gene was found in a mouse DNA array analysis of transcripts expressed in mouse preovulatory follicles.
Innate immunity in the human endometrium and ovary. Sheldon IM et al. Citation Sheldon IM, Bromfield JJ. Innate Immunity in the Human Endometrium and Ovary. Am J Reprod Immunol 2011; 66 (Suppl. 1): 63-71 Problem Microbial infections of the upper female genital tract perturb the function of the endometrium and ovary. Defense of these tissues is predominantly dependent on innate immunity. This review gives a perspective on innate immunity in the non-pregnant upper female genital tract of women. Method of study Literature review of innate immunity in the human endometrium and ovary. Results The endometrium is defended against microbes by physical barriers, antimicrobial peptides, complement, Toll-like receptors (TLRs), and other pattern recognition receptors. Endometrial epithelial and stromal cells express TLRs, which sense pathogen-associated molecular patterns (PAMPs), leading to an inflammatory response with the influx of neutrophils and macrophages. Innate immunity in the endometrium is regulated by steroids, eicosanoids, and cytokines. Granulosa cells also express TLRs and respond to PAMPs. Conclusion Pattern recognition receptors have roles in endometrial and ovarian inflammation, and innate immunity is central to the defense of the endometrium against pathogens.
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. This protein is a cell-surface protein that can form heterodimers with other TLR family members to recognize conserved molecules derived from microorganisms known as pathogen-associated molecular patterns (PAMPs). Activation of TLRs by PAMPs leads to an up-regulation of signaling pathways to modulate the host's inflammatory response. This gene is also thought to promote apoptosis in response to bacterial lipoproteins. This gene has been implicated in the pathogenesis of several autoimmune diseases. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
General function
Receptor
Comment
Mumps virus induces innate immune responses in mouse ovarian granulosa cells through the activation of Toll-like receptor 2 and retinoic acid-inducible gene I. Wang Q et al. (2016) Mumps virus (MuV) infection may lead to oophoritis and perturb ovarian function. However, the mechanisms underlying the activation of innate immune responses to MuV infection in the ovary have not been investigated. This study showed that Toll-like receptor 2 (TLR2) and retinoic acid-inducible gene I (RIG-I) cooperatively initiate innate immune responses to MuV infection in mouse ovarian granulosa cells. Ovarian granulosa cells infected with MuV significantly produced pro-inflammatory cytokines and chemokines, including interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), monocyte chemotactic protein 1 (MCP-1), and type 1 interferons (IFN-α and IFN-β). Knockdown of RIG-I significantly decreased MuV-induced cytokine expression. TLR2 deficiency reduced the expression of IL-1β, TNF-α, and MCP-1 but did not affect the expression of IFN-α and IFN-β in granulosa cells after infection with MuV. Intraperitoneal injection of MuV induced the ovarian innate immune responses in vivo, which suppressed estradiol synthesis and induced granulosa cell apoptosis. The results provide novel insights into the mechanisms underlying MuV-induced innate immune responses in the mouse ovary.//////////////////
Cellular localization
Plasma membrane
Comment
candidate123
Ovarian function
Steroid metabolism
Comment
Granulosa Cells from Emerged Antral Follicles of the Bovine Ovary Initiate Inflammation in Response to Bacterial Pathogen-Associated Molecular Patterns via Toll-Like Receptor Pathways. Price JC 2013 et al.
Bacterial infections of the uterus or mammary gland commonly perturb ovarian antral follicle growth and function, causing infertility in cattle. Cells of the innate immune system use Toll-like receptors TLR2, TLR4 and TLR5 to recognize pathogen-associated molecular patterns (PAMPs) of bacteria, leading to production of inflammatory mediators such as IL-1beta, IL-6, and IL-8. The present study examined whether granulosa cells from emerged antral follicles have functional responses to typical bacterial PAMPs. Granulosa cells from emerged bovine antral follicles expressed mRNA for all ten TLRs. Cellular expression of mRNA for the cytokines IL1B, IL6, IL10 and TNF, and chemokines IL8 and CCL5 increased after treatment with synthetic bacterial lipoprotein binding TLR2, lipopolysaccharide binding TLR4 or flagellin binding TLR5. Supernatants of granulosa cells accumulated IL-1beta, IL-6 and IL-8 protein in a concentration-dependent manner when treated with lipoprotein or lipopolysaccharide but not flagellin. Accumulation of IL-6 in response to lipoprotein and lipopolysaccharide was attenuated using siRNA targeting TLR2 and TLR4, respectively. Granulosa cells increased phosphorylation of MAPK14 and MAPK3/1 within 30 min of treatment with lipopolysaccharide or lipoprotein, and inhibitors targeting MAPK14 reduced the accumulation of IL-6 in response to the PAMPs. Treatment with hormones FSH, LH, estradiol or progesterone did not significantly affect granulosa cell responses to PAMPs. However, EGF enhanced IL-6 accumulation in response to lipoprotein and inhibiting EGFR abrogated the effect, whilst lipoprotein increased granulosa cell EGFR mRNA expression. In conclusion, bovine granulosa cells from emerged follicles sense bacterial PAMPs and initiate inflammatory responses via TLR2 and TLR4 pathways.
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Pathogen-associated molecular patterns initiate inflammation and perturb the endocrine function of bovine granulosa cells from ovarian dominant follicles via TLR2 and TLR4 pathways. Price JC 2013 et al.
Bacterial infections of the uterus or mammary gland commonly cause disease and infertility by perturbing growth and steroidogenesis of the dominant follicle in the ovary of cattle. Cells of the innate immune system use Toll-like receptors TLR2, TLR4 and TLR5 to recognize pathogen-associated molecular patterns (PAMPs) expressed by bacteria, leading to activation of MAPK and NF?B pathways, and production of inflammatory cytokines such as IL-1?and IL-6, and the chemokine IL-8. The present study tested whether granulosa cells from dominant follicles have functional TLR2, TLR4 and TLR5 pathways. Supernatants of primary bovine granulosa cells accumulated IL-1? IL-6 and IL-8 when treated for 24 h with PAM that binds TLR2 or LPS that binds TLR4, but not flagellin that binds TLR5. Granulosa cell responses to PAM or LPS were rapid, with increased phosphorylation of p38 and ERK1/2 within 30 min and increased abundance of IL6, IL1B, IL10, TNF, IL8 and CCL5 mRNA after 3 h treatment. Accumulation of IL-6 in response to PAM and LPS was attenuated using siRNA targeting TLR2 and TLR4, respectively. Furthermore, treating granulosa cells with inhibitors targeting MAPK or NF?B reduced the accumulation of IL-6 in response to LPS or PAM. Treatment with LPS or PAM reduced the accumulation of estradiol and progesterone, and the PAMPs reduced granulosa cell expression of CYP19A1 mRNA and protein. In conclusion, bacterial PAMPs initiate inflammation and perturb the endocrine function of bovine granulosa cells from dominant follicles via TLR2 and TLR4 pathways.Pr?s: A rapid inflammatory response to pathogen-associated molecular patterns mediated by TLR2 and TLR4 pathways in granulosa cells provides a molecular explanation of how bacterial infections distant to the ovary can perturb dominant follicle function.
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Expression regulated by
Comment
Ovarian localization
Cumulus, Granulosa, Theca, Follicular Fluid
Comment
Abnormal expression of TLRs may play a role in lower embryo quality of women with polycystic ovary syndrome. Gu BX et al. (2016) Toll-like receptors (TLRs) localize in mammalian ovary, including granulosa cells, cumulus cells, and theca cells. Previous studies demonstrated that TLRs may be important for the cumulus-oocyte complex expansion and fertilization. There is no evidence to indicate that the deletion of TLRs will induce infertility; however, the abnormal expression of TLRs may decrease oocyte quality and fertility rate. In the present study, we investigated the effects of polycystic ovary syndrome (PCOS) on the expression of TLRs in cumulus cells by using western-blot and quantitative real-time PCR (qRT-PCR) analyses. We found that the expression of TLR4 and 9 in cumulus cells was influenced significantly by PCOS. We also observed that overweight/obesity changed the expression of TLR2 and 5 in cumulus cells of PCOS subjects. In addition, we found that the rate of available embryos of women with PCOS was slightly lower. These results indicate that the abnormal expression of TLRs in cumulus may be a reason for the lower embryo quality of women with PCOS. ART: assisted reproductive technology BMI: body mass index COC: cumulus-cell-oocyte complex PCOS: polycystic ovary syndrome qRT-PCR: quantitative real-time PCR TLRs: Toll-like receptors.//////////////////
Toll-like receptors expression in follicular cells of patients with poor ovarian response. Taghavi SA 2014 et al.
BACKGROUND
Poor ovarian response (POR) to gonadotropin stimulation has led to a significant decline in success rate of fertility treatment. The immune system may play an important role in pathophysiology of POR by dysfunctions of cytokines and the growth factor network, and the presence of ovarian auto-antibodies. The aim of this study is to investigate the expression of toll-like receptors (TLR) 1, 2, 4, 5, 6 and cyclooxygenase (COX) 2 genes in follicular cells and concentration of interleukin (IL)-6, IL-8 and macrophage migration inhibitory factor (MIF), as major parts of innate immunity, in follicular fluid (FF) obtained from POR women in comparison with normal women.
MATERIALS AND METHODS
In this case-control study, 20 infertile POR patients and 20 normal women took part in this study and underwent controlled ovarian stimulation. The FF was obtained from the largest follicle (>18 mm). The FF was centrifuged and cellular pellet was then used for evaluation of expression of TLRs and COX2 genes by real-time PCR. FF was used for quantitative analysis for IL-6, IL-8 and MIF by enzyme-linked immunosorbent assay (ELISA).
RESULTS
TLR1, 2, 4, 5, 6 and COX2 gene expression were significantly higher in POR (p<0.05). Concentration of IL-6, IL-8 and MIF proteins was significantly increased in POR compared with normal women (p<0.05).
CONCLUSION
These findings support the hypothesis that the immune system may be involved in pathophysiology of POR through TLRs.
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Changes in the Expression of Toll-Like Receptor mRNAs During Follicular Growth and in Response to Lipopolysaccharide in the Ovarian Follicles of Laying Hens. Subedi K et al. The aim of this study was to determine the changes in the mRNA expression of Toll-like receptors (TLRs) in hen ovarian follicles during follicular growth and in response to lipopolysaccharide (LPS). White follicles and the fifth largest to largest follicles (WF and F(5)-F(1), respectively) were collected from laying hens. To examine the effects of LPS, the laying hens were treated intravenously with LPS (1 mg/kg BW) 0, 3, 6, 12 and 24 h before examination. Expressions of TLRs and IL-1 beta in the theca and granulosa layers were examined by semi-quantitative RT-PCR. Immunocytochemistry was performed to identify immunoreactive TLR-4. The theca layer expressed TLR-2, TLR-4, TLR-5 and TLR-7, whereas the granulosa layer expressed only TLR-4 and TLR-5. The expression of TLR-4 and TLR-5 in the theca layer increased significantly during follicular growth. In the granulosa layer, the expression of TLR-5 increased, but that of TLR-4 was unchanged. Expression of TLR-4 increased significantly during the period of 6 to 12 h of LPS treatment in the theca layer and during the period of 12 to 24 h in the granulosa layer of F(3). Immunoreaction products for TLR-4 were observed in theca interna and granulosa layers of WF and F(5)-F(1), with the greater amount observed in the theca interna. LPS treatment significantly increased expression of IL-1beta in the theca layer after 3 h and in the granulosa layer during the period of 12 to 24 h. These results suggest that TLRs are expressed in ovarian follicles and that TLR-4 and TLR-5 expression increases with the growth of follicles. Enhanced expression of TLR-4 and IL-1beta by LPS in the theca and granulosa layers suggests possible roles of TLR in recognition of microorganisms.
Follicle stages
Antral
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: human
Mutation name: type: naturally occurring fertility: subfertile Comment: Association of TLR2 S450S and ICAM1 K469E polymorphisms with polycystic ovary syndrome (PCOS) and obesity. Ojeda-Ojeda M et al. (2015) Toll-like receptors (TLRs) are activated by inflammatory stimuli and influence endothelial functions, contributing to the pathogenesis of atherosclerosis. We investigate the influence of polymorphisms in the genes encoding toll-like receptor 2 (TLR2) and 4 (TLR4) and endothelial adhesion molecules on polycystic ovary syndrome (PCOS) and its interaction with obesity. Ten single nucleotide polymorphisms were genotyped in 305 women with PCOS and 166 non-hyperandrogenic control women. In obese women, TLR2 S450S and ICAM1 K469E polymorphisms differently influenced metabolic variables and PCOS, respectively. Irrespective of PCOS, variant alleles of TLR2 S450S increased triglycerides, fasting insulin levels, and insulin resistance in obese women. TLR2 S450S interacted with obesity and PCOS on androstenedione levels, mutant alleles were associated with increased androstenedione concentrations in all women, with the exception of obese patients with PCOS (P=0.034). Regarding ICAM1 K469E, homozygosis for K469 alleles was more frequent in PCOS, but only in obese women (P=0.014). K469 alleles were also related to increased body mass index (P=0.017) and diastolic blood pressure (P=0.034). Moreover, ICAM1 K469E interacted with obesity and PCOS on serum triglyceride levels (P=0.019) and with PCOS on serum sex hormone-binding globulin concentrations (P=0.006). In conclusion, TLR2 S450S and ICAM1 K469E polymorphisms may be associated with PCOS and metabolic comorbidities in obese women.//////////////////