Differential effects of lipopolysaccharide and thrombin on interleukin-8 expression in syncytiotrophoblasts and...

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.