Interleukin-10 receptors are expressed by basement membrane anchored, alpha6 integrin+ cytotrophoblast cells in early human placenta

Abstract

Cytotrophoblast cells produce interleukin (IL)-10 and express IL-10 receptor mRNA in culture. Furthermore, IL-10 dramatically reduces the synthesis of matrix metalloproteinase (MMP)-9 and the invasivity of cytotrophoblast cells in vitro, suggesting that an autocrine regulatory role in vivo is also possible. To test this hypothesis we investigated the expression of IL-10 receptor protein by first trimester cytotrophoblasts both in vitro and in situ, using flow cytometry and immunohistochemistry. Flow cytometric analyses demonstrated that 75-80% of cytotrophoblasts are able to bind labelled IL-10, suggesting that these cells possess IL-10 receptors in vitro. Serial sections of early human placentae stained for either alpha(5) and alpha(6) integrin subunits, or for IL-10 receptors respectively, revealed that placental cytotrophoblasts possess cell surface IL-10 receptors not only in vitro, but also in vivo. IL-10 receptors were present mainly on alpha(6) integrin expressing villous cytotrophoblast cells and on alpha(6)-positive cells of invasive cell columns located nearest the villous stroma. Differentiated trophoblasts (i.e. alpha(5)-positive cells and villous syncytiotrophoblasts) showed no reactivity. This differential expression of IL-10 receptors suggests that IL-10 might suppress the invasivity of undifferentiated cytotrophoblast cells, in vivo, preserving their non-invasive state in an autocrine manner. The possible involvement in cytotrophoblast proliferation and/or differentiation is also discussed.

The activating effect of IFN-γ on monocytes/macrophages is regulated by the LIF–trophoblast–IL-10 axis via Stat1 inhibition and Stat3 activation

“…38 IL-10 mRNA expression was studied using RT-PCR to validate the use of BeWo cells as a pertinent model for studying the influence of villous cytotrophoblast-derived factors, such as IL-10, on the functional phenotype of pro-inflammatory Mws. As expected, 28,29 undifferentiated BeWo cells express basal levels of IL-10 mRNA. However, we found that the IL-10/GAPDH ratio substantially increased from 0.260.1 to 0.760.…”

“…55 Several lines of evidence suggest that IL-10 is an important suppressor of active maternal immunity that may be involved in the process of acceptance of the fetal allograft. 19,20,28,29 IL-10 levels increase markedly in women during early pregnancy and remain elevated up to the third trimester immediately prior to the onset of labor. Of note, compared to syncytiotrophoblasts, extravillous cytotrophoblasts are intrinsically poor in IL-10 production, 28,29 indicating that the syncytium might indeed contribute locally to counteract the deleterious effects of pro-inflammatory cytokines during early pregnancy.…”

“…27 Another important gestational factor is IL-10, which is a type-2 cytokine that is expected to play a key role in pregnancy immunotolerance through the establishment of a Th2 immune response at the maternal2fetal interface. 28,29 IL-10 inhibits the production of several pro-inflammatory cytokines, including TNF-a in Mws and IFN-c in NK cells, thereby preventing the development of type-1 immune reactions that are deleterious for both the establishment and maintenance of pregnancy. [30][31][32] Thus, using the IL-10 KO mice model to study LPS-induced preterm parturition, Murphy et al 19,20 demonstrated that in the absence of IL-10, IFN-c-producing uNK cells may exert cytotoxic functions through TNF-a production and invasiveness into the placental zone, leading to fetal demise or intrauterine fetal growth restriction.…”

“…19,20 Moreover, IL-10 is noted for its abilities to inhibit Mw proliferation by activating Stat3 33 and Trophoblast-mediated deactivation of macrophages A Dallagi et al to suppress IFN-c-mediated functions of Mws by blocking Stat1 activation. 34 In the pregnant human uterus, IL-10 is produced in large amounts by both the syncytiotrophoblast and the decidual Mws, 9,10,28,29 while LIF is highly expressed by decidual Mws and uNK cells. 35 On the other hand, the IL-10 receptor is constitutively expressed on placental trophoblasts 28,29 and decidual Mws are known to be highly responsive to IL-10.…”

“…34 In the pregnant human uterus, IL-10 is produced in large amounts by both the syncytiotrophoblast and the decidual Mws, 9,10,28,29 while LIF is highly expressed by decidual Mws and uNK cells. 35 On the other hand, the IL-10 receptor is constitutively expressed on placental trophoblasts 28,29 and decidual Mws are known to be highly responsive to IL-10. 9,10 In contrast, the expression level of LIF receptors is significantly higher in both villous and extravillous trophoblasts than in the decidua, 35 suggesting that all cells of the trophoblast lineage are major targets for the action of LIF in the placenta.…”