Recently, TLR4 expression was shown at the amniotic epithelium, and the strongest immunoreactivity for TLR4 was observed at basal membrane in CAM patients. The authors suggested that an infection may induce the translocation of TLR4 from apical to basal membrane to decrease TLR signaling during early infection but allow the amniotic epithelium to remain competent to invasive bacteria.42 In addition to CAM, we also INCB024360 in vivo evaluated the involvement of TLRs in the etiology of pre-eclampsia. Thus, TLR4 expression in trophoblast was significantly higher in women with preterm delivery associated with pre-eclampsia
than in women with or without CAM preterm delivery. Furthermore, TLR4 expression was co-localized with activated NFκB, TNF-α and M30 (an apoptosis marker specific for epithelial cells), suggesting that inflammatory cytokines can induce TLR4 expression and thereby enhance further trophoblast
response to TLR ligands.49 Similarly, Wang check details and coworkers78 described a correlation between high levels of TLR4 expression in microvessel endothelial cells isolated from placental villi, and placental vascular disease, defined by an abnormal umbilical artery Doppler study. These findings imply that the level of TLR expression in zthe placenta is controlled by certain pathogen per se and/or endogenous molecule produced upon inflammation, as a feedback mechanism to enhance or inhibit further immune responses, although precise mechanisms are not clarified yet. A new aspect on TLR function
is related to its ability to recognize not only microbial ligands but also host products, also know as ‘danger signals’ released by injured cells,79 suggesting that TLRs might be involved not only in infection but also in non-infection-related conditions associated with pregnancy. For instance, Holmlund et al.80 demonstrated that HMGB1, a ligand for TLR4, is highly expressed in decidua from pre-eclamptic patients. Anti-phospholipid antibodies, which is known to be involved in the pathology of recurrent miscarriage, pre-eclampsia and preterm labor, was also shown to induce a pro-inflammatory response in first-trimester trophoblast via TLR4 pathway.81 Given that the TLR system is involved in many pregnancy disorders, it is possible Inositol monophosphatase 1 that the TLR polymorphisms affect on the susceptibility to pregnancy disorders. Indeed, a number of studies evaluated whether polymorphisms in TLR are associated with pregnancy disorder. As for preterm labor, most of the studies are focusing on polymorphism in TLR2 and TLR4. Interestingly, not only polymorphism in the mother, but also that in the infant was analyzed and proved associations between fetal polymorphism and susceptibility to preterm labor. These findings imply that not only the immune system in the mother, but also that in the fetus or placenta contributes the innate immune response in preventing adverse outcomes in pregnancy.