Fgl2 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 associated with an increase in uterine T helper (Th) 1 type proinflammatory cytokines, tumour necrosis factor (TNF)-alpha, interferon-gamma and interleukin (IL)-1, and a deficiency of Th2/3 type cytokines, IL-4, IL-10, and transforming growth factor (TGF)-beta2. In mice, Th1 cytokines up-regulate a novel prothrombinase, fgl2, which via thrombin, leads to activation of polymorphonuclear leukocytes that terminate the pregnancy. Here we show that Th1 cytokines up-regulate fgl2 mRNA in fetal trophoblast and secondary decidua of CBA/JxDBA/2 and CBA/JxBALB/c matings, and promote fibrin deposition. This pattern is accompanied by a high rate of abortion. However, the spontaneous abortion rates in abortion-prone CBAxDBA/2 matings and in low abortion rate CBAxBALB/c matings were significantly lower than that expected from the frequency of implantations with high levels of fibrin and fgl2 mRNA(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 fgl2 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 reduced the abortion rate. Fgl2 prothrombinase may provide a mechanism explaining pregnancy loss, and conversely, successful pregnancy may be due in part to OX-2-dependent activation of maternal tolerance mechanisms at the feto-maternal interface.
Clark
D A
DA
Department of Medicine, Pathology & Molecular Medicine, and Department of Obstetrics & Gynecology, McMaster University, 1200 Main St West, Room 3V39, Hamilton, Ontario, Canada L8N 3Z5. clarkd@fhs.McMaster.ca
Ding
J W
JW
Yu
G
G
Levy
G A
GA
Gorczynski
R M
RM
D000022:Abortion, Spontaneous / Q000235:genetics* / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D015703:Antigens, CD; D000954:Antigens, Surface / Q000235:genetics*; D001483:Base Sequence; D016207:Cytokines / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D003656:Decidua / Q000378:metabolism*; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen; D015870:Gene Expression; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics*; D014327:Trophoblasts / Q000378:metabolism*
D015703:Antigens, CD; D000954:Antigens, Surface; D016207:Cytokines; D017931:DNA Primers; C095202:FGL2 protein, human; C490637:Fgl2 protein, mouse; D012333:RNA, Messenger; D005337:Fibrin; D005340:Fibrinogen; D013925:Thromboplastin; C042739:antigens, CD200