A Study of Toll-like Receptors in Trophoblasts, and the Influence of Cytomegalovirus Infection
MetadataVis full innførsel
Toll-like receptors (TLRs) act as sensors against invading pathogens and endogenous danger signals, and are critical mediators of inflammatory immune responses. During pregnancy, intrauterine activation of TLRs might evoke local inflammatory responses, resulting in the release of pro-inflammatory cytokines into maternal circulation. This culminates in the elimination of microbes and damaged host cells through recruitment and activation of immune cells, phagocytosis and autophagy. If the normal pregnancy-associated inflammation is escalated, it may provoke endothelial dysfunction and oxidative stress and subsequently affect placental implantation and function, possibly leading to the pathogenesis of inflammatory pregnancy disorders, such as preeclampsia and intrauterine growth restriction (IUGR). Traditionally, local maternal immune cells have been assigned the most active immunological role in the placenta. However, observations such as trophoblast expression of TLRs suggest that these fetal cells actively contribute to the inflammation at the maternal-fetal site both in normal pregnancy, inflammatory pregnancy disorders and in response to infections during pregnancy. Various in vitro studies, mainly of trophoblast choriocarcinoma cell lines and primary term trophoblasts, suggest that trophoblast TLRs are biological functional. In order to extend our knowledge on the relevance of TLR’s immunological role in trophoblasts, TLR gene expression and activation in primary first trimester trophoblasts were elucidated in response to specific TLR-ligands and infection with human cytomegalovirus (HCMV). Gene expression was analyzed by quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) and pro-inflammatory cytokine responses were determined by multiplex analysis. Trophoblast choriocarcinoma cell lines and fibroblasts were included for comparison. Overall, primary first trimester trophoblasts expressed several functionally active TLRs, indicating a more central role for trophoblast TLR-activation in inflammatory responses at the maternal-fetal interaction site than previously thought. Interestingly, primary first trimester trophoblasts expressed higher levels of TLRs and responded to TLR-activation with a more potent cytokine production compared to first trimester trophoblast cell lines. This substantiates a more potent immunological role for the first trimester trophoblasts than what is currently known based on cell line studies, and demonstrates the importance of functional studies in primary cells. HCMV induced immune activation in trophoblasts and fibroblasts, possibly involving TLRs. This reflects an immune potential and the ability of first trimester trophoblasts and fibroblasts to respond to viral infection.