Differential Effects of Lipopolysaccharide and Thrombin on Interleukin‐8 Expression in Syncytiotrophoblasts and Endothelial Cells: Implications for Fetal Survival

Abstract

Syncytiotrophoblasts (SCTs) are directly bathed by maternal blood and, as such, are in direct contact with proinflammatory stimuli present in the maternal circulation. The extent and nature of cytokine responses induced in SCTs play a central role in the maintenance of pregnancy. Thrombin is a critical mediator of tissue factor-initiated blood coagulation. Thrombin has been more recently demonstrated to induce cytokine expression and inflammation in several cell types. To dissect the patterns of regulation of cytokine production in the placental villus, we compared the effects of thrombin and lipopolysaccharide (LPS) treatments on cytokine expression in SCTs and endothelial cells. For studies, primary cultures of cytotrophoblasts from human term placentas were differentiated to SCTs. We observed that the presence of thrombin only modestly enhanced interleukin-8 (IL-8) levels in SCTs in a manner that was not dose-dependent. Conversely, SCTs were exquisitely sensitive to LPS, the presence of which induced approximately a 10-fold increase in IL-8 levels with an EC(50) approximately 1 ng/mL. Northern blotting and real-time PCR results indicated that LPS (but not thrombin) treatment induced a >4-fold increase in levels of IL-8 mRNA. The addition of the anti-inflammatory steroid, dexamethasone, significantly reduced the LPS-mediated increase in levels of IL-8 in SCTs. Conversely, in human umbilical vein endothelial cells, thrombin and LPS treatments induced 10- and 20-fold increases in IL-8 expression, respectively. These results indicate that LPS, but not thrombin, promotes proinflammatory processes in SCTs, with cell-type specificity. The inability of thrombin in the intervillous space to evoke inflammatory responses in SCTs may constitute an important aspect of fetal survival. Conversely, our results suggest that SCTs do play a key role in infection-associated changes in placental cytokine expression.

Cell Type-specific Expression and Function of Toll-like Receptors 2 and 4 in Human Placenta: Implications in Fetal Infection

“…Another group demonstrated increased TLR-4 expression in Hofbauer cells in pregnancies with chorioamnionitis [5], supporting a role for TLRs in this complication of pregnancy. We have also reported that LPS treatment enhances expression of pro-inflammatory cytokines by primary cultures of SCTs [32]. The current findings of differential patterns of TLR expression and function in SCTs, mFIBs, and endothelial cells (i.e.…”

Causal relationship between obesity-related traits and TLR4-driven responses at the maternal–fetal interface

“…It further supports our original hypothesis that ligand binding sites of placental TLR4 are readily accessible to factors derived from the maternal systemic circulation. An important finding is the localisation of TLR4 in the immediate perivascular region of placental–fetal vessels, which is in accordance with TLR4 expression in umbilical endothelial cells [30]. The human placental structure allows direct contact between the fetal vascular endothelial cells and fetal blood.…”

Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development

“…Thus, there are differential sensitivities of trophoblast cells to bacterial components across gestation. 63 This dose dependency and role for TLRs and NLRs is reflected in vivo. In pregnant mice, high-dose LPS induce placental and uterine inflammation, and subsequent preterm birth.…”