Problem-Preeclampsia is associated with hyperuricemia, which correlates with the disease severity. Levels of circulating uric acid increase before the clinical manifestations, suggesting they may be causally related. Uric acid, or monosodium urate (MSU), activates the Nod-like receptor, Nalp3, leading to inflammasome activation and IL-1β processing. Since preeclampsia is associated with placental immune/inflammatory dysregulation, we sought to determine in the trophoblast, the presence of the Nalp3 inflammasome, and the effect of MSU on its activation.Method of Study-Isolated first and third trimester trophoblast were assessed for expression of the inflammasome components, Nalp1, Nalp3 and ASC. First trimester trophoblast cells were incubated with or without MSU, after which, IL-1β secretion and processing and caspase-1 activation was determined.Results-Trophoblast cells expressed Nalp1, Nalp3 and ASC under basal conditions. Following incubation with MSU, first trimester trophoblast IL-1β secretion was upregulated. This correlated with increased expression levels of active IL-1β and active caspase-1. ASC knockdown reduced MSU-induced IL-1β secretion.Conclusion-These findings demonstrate that uric acid activates the inflammasome in the trophoblast, leading to IL-1β production. This may provide a novel mechanism for the induction of inflammation at the maternal-fetal interface leading to placental dysfunction and adverse pregnancy outcome, including preeclampsia.

In the legend of Figure 5 and in the text when referring to low molecular weight heparin (LMWH), the concentration of 10 lg ⁄ mL is incorrect. The correct LMWH concentration should be 100 lg ⁄ mL for all experiments. However, a lower dose of LMWH at 10 lg ⁄ mL was also able to reduce the upregulation of IL-8 triggered by the anti-b 2 GPI mAbs, ID2 and IIC5, but was not able to reverse the anti-b 2 GPI mAbs inhibition of trophoblast IL-6 secretion.Reference 1 Mulla MJ, Myrtolli K, Brosens JJ, Chamley LW, Kwak-Kim JY, Paidas MJ, Abrahams VM: Antiphospholipid antibodies limit trophoblast migration by reducing IL-6 production and STAT3 activity.

There is a strong association between infection and prematurity; however, the underlying mechanisms remain largely unknown. Nod1 and Nod2 are intracellular pattern recognition receptors that are activated by bacterial peptides and mediate innate immunity. We previously demonstrated that human first-trimester trophoblasts express Nod1 and Nod2, which trigger inflammation upon stimulation. This study sought to determine the expression and function of Nod1 and Nod2 in third-trimester trophoblasts, and to characterize the in vivo effects of Nod1 activation on pregnancy outcome. Human term placental tissues and isolated term trophoblast expressed Nod1, but not Nod2. Activation of Nod1 by its agonist, bacterial γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP), in term trophoblast cultures induced a proinflammatory cytokine profile, characterized by elevated levels of secreted IL-6, GRO-α, and MCP-1, when compared with the control. However, these cytokines were not upregulated in response to Nod2 stimulation with bacterial MDP. Administration of high-dose bacterial iE-DAP to pregnant C57BL/6J mice on embryonic day 14.5 triggered preterm delivery within 24 h. iE-DAP at a lower dose that did not induce prematurity, reduced fetal weight, altered the cytokine profile at the maternal–fetal interface, and induced fetal inflammation. Thus, functional Nod1 is expressed by trophoblast cells across gestation and may have a role in mediating infection-associated inflammation and prematurity. This study demonstrates that pattern recognition receptors, other than the TLRs, may be implicated or involved in infection-associated preterm labor.

This study demonstrates that aPL limit trophoblast cell migration by downregulating trophoblast IL-6 secretion and STAT3 activity. As heparin was unable to prevent these effects, our findings may explain why women with antiphospholipid syndrome, treated with heparin, remain at risk of developing obstetrical syndromes, associated with impaired deep placentation, such as pre-eclampsia.

Problem There is a strong correlation between intrauterine bacterial infection and preterm labor. While inflammation is a common mechanism, certain pathogens may trigger placental apoptosis. TLR2 activation by gram-positive bacterial peptidoglycan (PDG) induces first trimester trophoblast apoptosis and decreased IL-6 secretion. This is dependent upon the presence of TLR1 and the absence of TLR6, both TLR2 co-receptors. Since TLR10 is also a TLR2 co-receptor, the objective of this study was to determine its expression and function in the trophoblast. Method of Study First and third trimester human placental tissue and isolated trophoblast were evaluated for TLR10 expression. A first trimester human trophoblast cell line, stably transfected with a TLR10 dominant negative (TLR10-DN) or vector control was treated with or without PDG and analyzed for apoptosis and IL-6. Results TLR10 was expressed by trophoblasts during the first and third trimesters of pregnancy. PDG-induced trophoblast caspase-3 activity was inhibited by the presence of the TLR10-DN. The presence of the TLR10-DN had no effect on PDG- reduction in trophoblast IL-6 secretion. Conclusion This study demonstrates that trophoblast TLR10 plays a role in promoting apoptosis triggered by gram-positive bacterial components, and suggests that TLR10 may regulate the balance between trophoblast survival and cell death.