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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 11 (IL11) is maximally expressed in the
decidua, with its receptor, IL11 receptor alpha (IL11RA), also identified on invasive EVTs in vivo. Although a role for IL11
in EVT migration has been established, whether it also plays a role in regulating EVT invasion is unknown. We investigated
whether IL11 influences human EVT invasion and the signaling pathways and underlying mechanisms that may be involved, using
the HTR-8/SVneo immortalized EVT cell line and primary EVTs as models for EVTs. Interleukin 11 (100 ng/ml) significantly inhibited
invasion of EVT cells by 40% to 60% ( P < 0.001). This effect was abolished by inhibitors of signal transducer and activator of transcription 3 (STAT3) but not of
mitogen-activated protein kinase (MAPK) pathways. Interleukin 11 (100 ng/ml) had no effect on matrix metallopeptidases 2 and
9 (MMP2 and MMP9), tissue inhibitors of MMP (TIMP1, TIMP2, and TIMP3), plasminogen activator urokinase (PLAU), plasminogen
activator urokinase receptor (PLAUR), and serpin peptidase inhibitors 1 and 2 (SERPINE1 and SERPINE2) in EVT-conditioned media
and/or cell lysates. Interleukin 11 (100 ng/ml) also did not regulate EVT cell adhesion or integrin expression. These data
demonstrate that IL11 inhibits human EVT invasion via STAT3, indicating a likely role for IL11 in the decidual restraint of
EVT invasion during normal pregnancy.