Hormonal regulation of innate immune responses and toll-like receptors in the human endometrium

This study examines the cycle-dependent expression and hormonal regulation of TLRs in immune responses in the human reproductive tract. TLR expression could be significant as the reproductive tract is an important site of exposure to and infection with pathogens. The cytokine milieu is essential in normal functions of the human endometrium, including progression through the menstrual cycle, embryo implantation, and the establishment and maintenance of pregnancy. The reproductive tract is unique since it hormonally controls expression levels of soluble immune mediators and influx of immune cells to mediate these functions. Since TLRs have to the potential to induce alterations in cytokine production through recognition of specific ligands, TLR ligation could affect endometrial health. We demonstrated cycle-dependent expression of TLRs and several TLR-associated molecules in the endometrium. Specifically, we observed that TLR3 is expressed at high levels during the window of implantation, when the expression of all other TLRs and associated molecules examined is low. TLR3 recognizes dsRNA (the viral genome or a product viral replication) to induce proinflammatory and antiviral immune responses. xvii Thus, since the expression of pattern of TLR3 in the endometrium is unique in comparison to that of other TLRs and associated molecules, TLR3 may play a role in preparing the endometrium for implantation in addition to mediating proinflammatory and antiviral responses within the endometrium. We determined in this study that the cyclic expression of TLR3 within the endometrium is not due to a direct action of hormones on TLR3 mRNA or protein expression, but that hormones are able to affect TLR3 function through suppression of TLR3-mediated responses. These hormonal effects are dependent upon the expression of hormone receptors and appear to be acting at the level of TLR3-induced proinflammatory and antiviral gene transcription. The results of this study indicate that TLRs initiate immune responses to inflammatory stimuli in the human endometrium. TLR3 was determined to be a cyclically regulated protein specifically expressed during the window of implantation that can mediate antiviral immune responses and alter the cytokine milieu, potentially influencing the outcomes and consequences of infection. This suggests that TLR3 ligands may be utilized to develop treatment and vaccine strategies against viral pathogens in the endometrium, and identifies TLR3 as a possible target for treatment of endometrial dysfunctions such as endometriosis, infertility, and spontaneous abortion.