The innate immune response and toll-like receptors in the human endometrium

This study examines 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 functioning of the human endometrium such as progression through the menstrual cycle, embryo implantation, and pregnancy maintenance. 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 induce alterations in cytokine production, TLR ligation could affect endometrial health.;We detected mRNA expression of all TLRs except TLR10 in the human endometrial epithelium. Our data indicates that TLR7 and TLR8 are expressed as alternatively spliced variants that can be modulated by stimulation of TLR3. This suggests that TLR7 and TLR8 isoforms could be expressed and regulated by inflammatory stimuli. We found that TLR2, TLR4, and TLR5 are expressed, and that stimulation with the appropriate ligand induces proinflammatory responses.;TLR3 recognizes dsRNA (the viral genome or a product viral replication), to induce immune responses. We demonstrated cycle-dependent expression of TLR3 in the endometrium and established that dsRNA induces TLR3-dependent proinflammatory and antiviral responses and production of defensins. The defensins were cyclically expressed in non-stimulated endometrial epithelium, and we made the novel observation that HNP4 and HBD5 are cyclically expressed in the endometrium. Defensin expression was modulated by dsRNA stimulation. We additionally observed that the antiviral response in endometrial epithelial cells was altered. Secondary antiviral response genes were constitutively up-regulated, and responses to dsRNA stimulation were initially robust, while secondary responses appeared subdued.;The results of this study indicate that TLRs initiates immune responses to inflammatory stimuli in the human endometrium. TLR3 was determined to be a cyclically regulated protein 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.