223. Interleukin-11 inhibits human trophoblast invasion via STAT-3 and not MAPK, indicating a likely role in the decidual restraint of trophoblast invasion during placentation

Abstract

Successful pregnancy depends on the precise regulation of extravillous trophoblast (EVT) invasion into the uterine decidua, primarily by decidua-derived factors. In humans, during early pregnancy, interleukin (IL)-11 is maximally expressed in the decidua1, with its receptor, IL-11-receptor α (Rα) also identified on invasive EVT in vivo2. While a role for IL-11 in EVT migration has been established2, whether it also plays a role in regulating EVT invasion is unknown. We investigated whether IL-11 influences human EVT invasion and the signalling pathways and underlying mechanisms involved using the HTR-8/SVneo immortalised EVT cell-line and primary EVT as models for EVT. The effect of IL-11 on tyrosine phosphorylation (p) of signal transducer and activator of transcription (STAT)-3 was determined by Western Blot. EVT invasion was assessed using in vitro Matrigel invasion assays. To elucidate the mechanisms by which IL-11 may influence EVT invasion, matrix metalloproteinase (MMP) and urokinase plasminogen activator (uPA) activity were assessed by gelatin and plasminogen zymography / uPA activity assay respectively. Tissue inhibitor of MMPs (TIMPs)-1 and –2, plasminogen activator inhibitor (PAI)-1 and –2 and uPA receptor (uPAR) were assessed by ELISA whereas TIMP-3 was assessed by Western Blot. EVT adhesive properties and integrin expression were assessed by in vitro adhesion assays. IL-11 (100 ng/mL) significantly inhibited invasion of EVT cells by 40–60% (P < 0.001). This effect was abolished by inhibitors of STAT-3 but not of mitogen-activated protein kinase pathways. IL-11 (100 ng/mL) had no effect on MMP-2 and –9, TIMP 1–3, uPA, uPAR, PAI-1 and –2 in EVT conditioned media and / or cell lysates. IL-11 (100 ng/mL) also did not regulate EVT cell adhesion or integrin expression. These data demonstrate that IL-11 inhibits human EVT invasion via STAT-3 indicating an important role for IL-11 in the decidual restraint of EVT invasion during normal pregnancy. (1) Dimitriadis et al. (2003) Reprod Biol Endocrinol. 1, 34–38 (2) Paiva et al. (2007) Endocrinol. 148, 5566–72