Paper Information

Journal:   INTERNATIONAL JOURNAL OF FERTILITY AND STERILITY   SUMMER 2011 , Volume 5 , Number SUPPLEMENT 1; Page(s) 14 To 15.
 
Paper: 

FEMALE INFERTILITY: REPRODUCTION AND TOLL LIKE RECEPTORS (TLRS)

 
 
Author(s):  AFLATOONIAN R.*
 
* DEPARTMENT OF ENDOCRINOLOGY AND FEMALE INFERTILITY, REPRODUCTIVE BIOMEDICINE CENTER, ROYAN INSTITUTE FOR REPRODUCTIVE BIOMEDICINE, A.C.E.C.R., TEHRAN, IRAN
 
Abstract: 

Female and male reproductive tracts are of interest sites to study of immune system because they encounter specific infections such as those are sexually transmitted. Furthermore, female reproductive tract is in close contact with allogenic sperms and transmitted microorganisms during intercourse and semi allogenic fetus during pregnancy.
In mammals, there are two types of immune responses, the innate and the acquired immune responses. While acquired immune responses act later in an infection and are highly specific for the pathogen that induces them, the innate immune responses react immediately after exposure to pathogens and serve as the first line of host defense. The innate immune system depends on the pattern recognizing receptors (PRRs) including the Toll-like receptor (TLR) family that detect the pathogen-associated molecular patterns (PAMPs) and activate subsequent immune cell responses. TLRs can recognize a variety of PAMPs including lipoprotein, lipopolysaccharide (LPS), peptidoglycan, zymosan, bacterial flagella, CpG DNA, single and double strand RNAs. To date, ten human TLRs and thirteen mouse TLRs have been identified.
Several groups have reported the expression of TLRs in different tissues. Nevertheless, relatively little has been done to identify TLRs in the human female reproductive tract (FRT). Furthermore, some findings are controversial. In our recent works, we showed that TLR1-10 genes were expressed in human fallopian tube and endometrial tissue. The mean relative expression of some TLR genes was significantly higher during the secretory phase of the menstrual cycle in endometrium. Although these findings were in consist with previous works but some differences were shown as we found TLR10 gene expression in the endometrium. We also investigated TLR expression and function in three human endometrial epithelial cell lines, including hTERT-EEC, HEC-1B and Ishikawa cells and showed that TLR expression in these cell lines is comparable to published literature on TLR expression in primary human endometrial tissue. We also found that hTERT-EEC cells were responsive to TLR5 ligand and HEC-1B cells respond to TLR3 and TLR5 ligands. In contrast, Ishikawa cells respond only to PMA/I which was used as a positive control for IL-8 production. We also showed that the endometrial cell lines have a tendency for increased TLR5 expression in response to flagellin stimulation which was significant in hTERT-EEC cells.
On the other hand, determination and characterization of TLRs have been studied limited in the human male reproductive tract. Therefore, we investigated the expression of TLRs in different regions of male reproductive tract in our last research. In this research, RT-PCR was used to show the existence of all TLR genes exception TLR8 in the male reproductive tract, Q-PCR analysis used to investigate the relative expression of TLR2, 3 and 4 genes and immunoblot analysis was used for detect TLR2-4 on spermatozoa. The results showed that most intended TLRs except TLR4, 6,7and 10 in vasa deferens, TLR3 in Prepuce and TLR7 in Testis, are expressed in different parts of the human male reproductive tract. Existence of TLR2, 3 and 4 in spermatozoa has been shown by using western blot technique. However, related to TLRs that have not been expressed, additional experiments are needed.
TLRs function and expression were also investigated in certain tissues associated with pregnancy such as placenta and amnion. Different researches showed that normal term placental tissue expresses TLR1-10. Also it was shown that first trimester syncytiotrophoblast do not expressTLR2 and TLR4 in contrast to first-trimester placental tissues. Other researches in this regard showed that human first-trimester trophoblast secretion of chemokines is significantly increased following the ligation of TLR3 by poly (I:C) or TLR4 by bacterial LPS. However, anti-viral factors, such as interferon-
b and secretory leukocyte protease inhibitor seem to be produced by these cells following stimulation with poly I:C (TLR3- specific ligand), but not TLR4 ligand (LPS). In addition, it was shown that although TLR3 and TLR4 ligation promote cytokine production in first-trimester trophoblast cells, it seems ligation of TLR2 in these cells induces apoptosis. This TLR2-mediated trophoblast apoptosis may provide a novel mechanism of pathogenesis by which certain intra-uterine infections may contribute to conditions such as preterm labour, intra uterine growth restriction (IUGR), spontaneous abortion and preeclampsia. Expression of all ten TLRs is shown in first trimester and term deciduas. For amnion, it was reported that both TLR2 and TLR4 are expressed by amniotic epithelial cells. Also the soluble form of TLR2 was demonstrated in amniotic fluid.
As implantation is one of key steps in reproduction, we recently used two cell lines (hTERT-EECs and JAr cells) and provided an in vitro model for studying human implantation. We showed that treatment of endometrial cells with TLR5 ligand (flagellin) suppresses the attachment of JAr spheres to the endometrial cells while usage of TLR5 function blocking antibody restores the attachment of JAr spheres to endometrium. Consequently, further studies are needed to explore other mechanisms by which the presence of intrauterine infections may result in implantation failure.
Studying the function of TLRs in the female reproductive tract presents an exciting opportunity to further understand the regulation of innate immune system in the female reproductive tract. It seems sex hormones regulate the function and expression of TLRs in the female reproductive tract and therefore influence/regulate innate and adaptive immune function in this tract to protect against potential pathogens while providing an environment that supports an allogeneic fetus. How TLR function and expression is exactly regulated in reproductive tract by sex hormones would be a challenging but fruitful area of future research.

 
Keyword(s): TOLL-LIKE RECEPTOR, MALE REPRODUCTIVE TRACT, FEMALE REPRODUCTIVE TRACT, IMPLANTATION, PREGNANCY
 
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