2658-6533Research Results in Biomedicine2658-653310.18413/2313-8955-2018-4-3-0-11502GeneticsEXPRESSION OF TOLL-LIKE RECEPTORS IN THE FEMALE REPRODUCTIVE TRACT AND ITS HORMONE REGULATION (REVIEW)EXPRESSION OF TOLL-LIKE RECEPTORS IN THE FEMALE REPRODUCTIVE TRACT AND ITS HORMONE REGULATION (REVIEW)LebedevaOlga P.LebedevaOlga P.safonova2@yandex.ruQirkoRobertQirkoRobert20184300

Background: Toll-like receptors (TLR) are the main receptors of the innate immune system, recognizing ligands of bacteria, viruses, fungi and protozoa and inducing immune response. However, complex reviews of new data about expression and function of TLR in all organs of the female reproductive tract (including fallopian tubes and ovaries) and its hormone regulation have not been carried out. The aim of the study:  To perform an up-to-date review of the literature concerning expression of TLR in the vagina, ecto- and endocervix, uterus, fallopian tubes and ovaries and its hormone regulation. Materials and methods: The analysis of publications over the past 20 years in databases Pubmed, Google Academy, Scopus, Elibrary, ResearchGate, EBSCO has been carried out. Results: The review presents new data on the expression of TLR in the vagina, ecto- and endocervix, uterus, fallopian tubes and ovaries. The role of TLR is described not only in inducing an immune response and providing protection against infections, but also in regulating the capitation of spermatozoa and in fertilization. The effect of sex hormones (estradiol, progesterone) on expression and TLR function is estimated. Conclusion: TLR expression was found in all organs of the female reproductive tract. Expression of TLR is under the influence of sex hormones and is the maximum in the secretory phase of the menstrual cycle. TLR take part not only in defense of the reproductive tract against infections, but also in reproduction (capacitation of spermatozoa, fertilization, protection of gametes and embryos).

Background: Toll-like receptors (TLR) are the main receptors of the innate immune system, recognizing ligands of bacteria, viruses, fungi and protozoa and inducing immune response. However, complex reviews of new data about expression and function of TLR in all organs of the female reproductive tract (including fallopian tubes and ovaries) and its hormone regulation have not been carried out. The aim of the study:  To perform an up-to-date review of the literature concerning expression of TLR in the vagina, ecto- and endocervix, uterus, fallopian tubes and ovaries and its hormone regulation. Materials and methods: The analysis of publications over the past 20 years in databases Pubmed, Google Academy, Scopus, Elibrary, ResearchGate, EBSCO has been carried out. Results: The review presents new data on the expression of TLR in the vagina, ecto- and endocervix, uterus, fallopian tubes and ovaries. The role of TLR is described not only in inducing an immune response and providing protection against infections, but also in regulating the capitation of spermatozoa and in fertilization. The effect of sex hormones (estradiol, progesterone) on expression and TLR function is estimated. Conclusion: TLR expression was found in all organs of the female reproductive tract. Expression of TLR is under the influence of sex hormones and is the maximum in the secretory phase of the menstrual cycle. TLR take part not only in defense of the reproductive tract against infections, but also in reproduction (capacitation of spermatozoa, fertilization, protection of gametes and embryos).

toll-like receptorsTLRinnate immunityinfectionscapacitationfertilizationestradiolprogesteronetoll-like receptorsTLRinnate immunityinfectionscapacitationfertilizationestradiolprogesteroneСписок литературыIwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science. 2010;327(5963):291-295.Sheldon IM, Owens SE, Turner ML. Innate immunity and the sensing of infection, damage and danger in the female genital tract. Journal of reproductive immunology. 2017;119:67-73.Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nature immunology. 2015;16(4):343-353.Lebedeva OP, Kalutsky PV, Pakhomov SP, et al. [Toll-like receptors and their ligands] Scientific bulletin of Belgorod State University: Medicine and Pharmacy. 2010;12(22):31-35. Russian.Tukhvatullin AI, Logunov DY, Scherbinin DN, et al. [Toll-like receptors and their accessory molecules. Review]. Biochemistry (Moscow). 2010;75(9):1224-1243. Russian.Pandey S, Kawai T, Akira S. Microbial sensing by toll-like receptors and intracellular nucleic acid sensors. Cold Spring Harbor perspectives in biology. 2015;7(1):a016246.Amjadi F, Zandieh Z, Salehi E, et al. Variable localization of Toll-like receptors in human fallopian tube epithelial cells. Clinical and experimental reproductive medicine. 2018;45(1):1-9.Guan Y, Ranoa DRE, Jiang S, et al. Human TLRs 10 and 1 share common mechanisms of innate immune sensing but not signaling. The Journal of Immunology.2010;184(9):5094-5103.Khaitov RM, Yarilin AA, Pinegin BV. [Immunology: an atlas]. Moscow: GEOTAR-Media; 2011. Russian.Lebedeva OP. [Prognosis, early diagnosis and prophylaxis of complications of gestation process, resulting from infectious inflammation]Russian.Lebedeva OP, Pakhomov SP, Karpov PA, et al. [Significance of the innate immunity of toll-like receptors in the development of obstetric and gynecological disorders]. International Journal of immunopathology, allergology and infectology. 2012;1:19-26. Russian.Kannaki TR, Shanmugam M, Verma PC. Toll-like receptors and their role in animal reproduction. Anim Reprod Sci 2011;125:1-12.Lebedeva O, Pakhomov S, Ivashova O, et al. Expression of TLR1-10 and caspase-3 alfa at women with early miscarriages. Giornale Italiano di Ostetricia e Ginecologia. 2013;35(1):270-271.Liu Z, Shimada M, Richards JS. The involvement of the Toll-like receptor family in ovulation. J Assist Reprod Genet. 2008;25:223-8.Nasu K, Narahara H. Pattern recognition via the Toll-like receptor system in the human female genital tract. Mediators Inflamm. 2010;2010:976024.Shimada M, Hernandez-Gonzalez I, Gonzalez-Robanya I, et al. Induced expression of pattern recognition receptors in cumulus oocyte complexes: novel evidence for innate immune-like functions during ovulation. Mol Endocrinol. 2006;20:3228-39.Zandieh Z, Amjadi F, Ashrafi M, The effect of estradiol and progesterone on Toll like receptor gene expression in a human fallopian tube epithelial cell line. Cell Journal (Yakhteh). 2016;17(4):678-91.Pioli PA, Amiel E, Schaefer TM, et al. Differential expression of Toll-like receptors 2 and 4 in tissues of the human female reproductive tract. Infect Immun. 2004;72:5799-806.Hart KM, Murphy AJ, Barrett KT, et al. Functional expression of pattern recognition receptors in tissues of the human female reproductive tract. Journal of Reproductive Immunology. 2009;80(1-2):33-40.Wira CR, Rodriguez-Garcia M, Patel MV. The role of sex hormones in immune protection of the female reproductive tract. Nature reviews Immunology. 2015;15(4):217-30.Aflatoonian R, Fazeli A. Toll-like receptors in female reproductive tract and their menstrual cycle dependent expression. J Reprod Immunol. 2008;77(1):7-13.Schaefer TM, Desouza K, Fahey JV, et al. Toll-like receptor (TLR) expression and TLR-mediated cytokine/chemokine production by human uterine epithelial cells. Immunology. 2004;112:428-36.Sheldon IM, Bromfield JJ. Innate immunity in the human endometrium and ovary. American Journal of Reproductive Immunology. 2011;66(s1):63-71.Young SL, Lyddon TD, Jorgenson RL, et al. Expression of toll-like receptors in human endometrial epithelial cells and cell lines. Am J Reprod Immunol 2004;52:67-73.Hirata T, Osuga Y, Hamasaki K, et al. Expression of toll-like receptors 2, 3, 4, and 9 genes in the human endometrium during the menstrual cycle. J Reprod Immunol. 2007;74:53-60.Hirata T, Osuga Y, Hirota Y, et al. Evidence for the presence of Toll-like receptor 4 system in the human endometrium. J Clin Endocrinol Metab. 2005;90(1):548-556.Schaefer TM, Fahey JV, Wright JA, et al. Innate immunity in the human female reproductive tract: antiviral response of uterine epithelial cells to the TLR3 agonist poly(I:C). J Immunol. 2005;174:992-1002.Aflatoonian R, Tuckerman E, Elliott SL, et al. Menstrual cycle-dependent changes of Toll-like receptors in endometrium. Hum Reprod. 2007;22:586-593.Fazeli A, Bruce C, Anumba DO. Characterization of Toll-like receptors in the female reproductive tract in humans. Human Reproduction. 2005;20(5):1372-1378.Allhorn S, Boing C, Koch AA, et al. TLR3 and TLR4 expression in healthy and diseased human endometrium. Reprod Biol Endocrinol 2008;6:40.Crane-Godreau MA, Wira CR. CCL20/macrophage inflammatory protein 3α and tumor necrosis factor alpha production by primary uterine epithelial cells in response to treatment with lipopolysaccharide or Pam3Cys. Infection and Immunity. 2005;73(1): 476-484.Aboussahoud W, Aflatoonian R, Bruce C, et al. Expression and function of Toll-like receptors in human endometrial epithelial cell lines. Journal of reproductive immunology. 2010;84(1):41-51.Lyons RA, Saridogan E, Djahanbakhch O. The reproductive significance of human fallopian tube cilia. Hum Reprod Update. 2006;12:363-72.Vasilevskaya LN. [Gynaecology: a tutorial]. Rostov-on-Don: Phoenix; 2009. Russian.Itoh H, Nasu K, Nishida M, et al. Human oviductal stromal fibroblasts, but not oviductal epithelial cells, express Toll-like receptor 4: the site- specific mucosal immunity of the human fallopian tube against bacterial infection. Am J Reprod Immunol. 2006;56(2):91-101.Ghosh M, Schaefer TM, Fahey JV, et al. Antiviral responses of human fallopian tube epithelial cells to Toll-like receptor 3 agonist poly(I:C). Fertil Steril. 2008;89(5 Suppl):1497-506.Zandieh Z, Ashrafi M, Jameie B, Evaluation of immunological interaction between spermatozoa and fallopian tube epithelial cells. Andrologia. 2015;47:1120-30.Du MR, Wang SC, Li DJ. The integrative roles of chemokines at the maternal-fetal interface in early pregnancy. Cell Mol Immunol. 2014;11:438-48.Dechanet C, Anahory T, Mathieu Daude JC, et al. Effects of cigarette smoking on reproduction. Human Reproduction Update. 2011;17(1):76-95.Raidt J, Werner C, Menchen T, et al. Ciliary function and motor protein composition of human fallopian tubes. Hum Reprod. 2015;30:2871-80.O’Doherty AM, Di Fenza M, Kolle S. Lipopolysaccharide (LPS) disrupts particle transport, cilia function and sperm motility in an ex vivo oviduct model. Sci Rep. 2016;6:24583.Karimi K, Sarir H, Mortaz E, et al. Toll-like receptor-4 mediates cigarette smoke-induced cytokine production by human macrophages. Respiratory research. 2006;7(1):66.Zhou M, McFarland-Mancini MM, Funk HM, Toll-like receptor expression in normal ovary and ovarian tumors. Cancer Immunol Immunother. 2009;58:1375-1385.Gu BX, Wang X, Yin BL, et al. Abnormal expression of TLRs may play a role in lower embryo quality of women with polycystic ovary syndrome. Systems biology in reproductive medicine. 2016;62(5):353-358.Shimada M, Yanai Y, Okazaki T, et al. Hyaluronan fragments generated by sperm-secreted hyaluronidase stimulate cytokine ⁄ chemokine production via the TLR2 and TLR4 pathway in cumulus cells of ovulated COCs, which may enhance fertilization. Development. 2008;135:2001-2011.Richards JS. Ovulation: new factors that prepare the oocyte for fertilization. Mol Cell Endocrinol. 2005;234:75-79.Hoshino K, Takeuchi O, Kawai T, et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the LPS gene product. J Immunol. 1999;162:3749-3752.Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H ⁄ HeJ and C57BL ⁄ 10ScCr mice: mutations in Tlr4 gene. Science. 1998;282:2085-2088.Besnard N, Horne EA, Whitehead SA. Prolactin and lipopolysaccharide treatment increased apoptosis and atresia in rat ovarian follicles. Acta Physiol Scand 2001;172:17-25.Taylor CC, Terranova PF. Lipopolysaccharide inhibits in vitro luteinizing hormone-stimulated rat ovarian granulosa cell estradiol but not progesterone secretion. Biol Reprod. 1996;54:1390-1396.Fishel S, Jackson P, Webster J, et al. Endotoxins in culture medium for human in vitro fertilization. Fertil Steril. 1988;49:108-111.Taghavi SA, Ashrafi M, Mehdizadeh M, Toll-like receptors expression in follicular cells of patients with poor ovarian response. International journal of fertility and sterility. 2014;8(2):183-192.Jorgenson RL, Young SL, Lesmeister MJ, et al. Human endometrial epithelial cells cyclically express Toll-like receptor 3 (TLR3) and exhibit TLR3-dependent responses to dsRNA. Hum. Immunol. 2005;66:469-482.Lin Z, Xu J, Jin X, et al. Modulation of expression of Toll-like receptors in the human endometrium. Am. J. Reprod. Immunol. 2009;61:338-345.Lesmeister MJ, Jorgenson RL, Young SL, et al. 17beta-estradiol suppresses TLR3-induced cytokine and chemokine production in endometrial epithelial cells. Reproductive Biology and Endocrinology. 2005;3:74.Wagner R, Johnson S. Probiotic lactobacillus and estrogen effects on vaginal epithelial gene expression responses to Candida albicans. J. Biomedi. Sci. 2012;19:58.Ghisletti S, Meda C, Maggi A., et al. 17β-Estradiol inhibits inflammatory gene expression by controlling NF-κB intracellular localization. Mol. Cell Biol. 2005;25:2957-2968.Murphy AJ, Guyre PM, Pioli PA. Estradiol suppresses NF-κB activation through coordinated regulation of let-7a and miR-125b in primary human macrophages. J. Immunol. 2010;184:5029-5037.Taggart CC, Cryan SA, Weldon S, et al. Secretory leucoprotease inhibitor binds to NF-κB binding sites in monocytes and inhibits p65 binding. J. Exp. Med. 2005;202:1659-1668.Dennison U, McKernan DP, Scully P, et al. Menstrual Cycle Influences Toll-Like Receptor Responses. Neuroimmunomodulation. 2012;19:171-179.