Fg12 prothrombinase expression in mouse trophoblast and decidua triggers abortion but may be countered by OX-2

Spontaneous abortion of normal karyotype embryos in mice and in humans is a ssociated with an increase in uterine T helper (Th) 1 type proinflammatory cytokines, tumour necrosis factor (TNF)-alpha, interferon-gamma and interle ukin (IL)-1, and a deficiency of Th2/3 type cytokines, IL-4, IL-10, and tra nsforming growth factor (TGP)-beta2. In mice, Th1 cytokines up-regulate a n ovel prothrombinase, fgl2, which via thrombin, leads to activation of polym orphonuclear leukocytes that terminate the pregnancy. Here we show that Th1 cytokines up-regulate fgl2 mRNA in fetal trophoblast and secondary decidua of CBA/J x DBA/2 and CBA/J x BALB/c matings, and promote fibrin deposition . This pattern is accompanied by a high rate of abortion. However, the spon taneous abortion rates in abortion-prone CBA x DBA/2, matings and in low ab ortion rate CBA x BALB/c matings were significantly lower than that expecte d from the frequency of implantations with high levels of fibrin and fgl2 m RNA(hi). As the glycoprotein OX-2 occurs in the pregnant rat uterus and can deviate cytokine responses to Th2/3, we investigated OX-2 in pregnant CBA/ J mice. We found OX-2 mRNA was present at the same sites as fg12 mRNA, but was reduced in response to Th1 cytokines, Furthermore, anti-OX-2 raised the abortion rate to predicted levels, while recombinant OX-2 dramatically red uced the abortion rate. Fgl2 prothrombinase may provide a mechanism explain ing pregnancy loss, and conversely, successful pregnancy may be due in part to OX-2-dependent activation of maternal tolerance mechanisms at the fete- maternal interface.