Summary. In this study, we examined the effect of injecting various cytokines. We report here that tumour necrosis factor (TNF)\g=a\,\g=g\-interferon and interleukin 2 (IL-2) can, in some circumstances, increase fetal resorption rates in abortionprone (CBA/J \m=x\DBA/2) and non-abortion prone (CBA/J \m=x\BALB/c,C3H \m=x\DBA/2) matings: 1000 units TNF enhanced resorptions from 43 to 79% in CBA \m=x\DBA/2, from 7 to 89% in CBA \m=x\ BALB/c, from 5 to 47% in C3H \m=x\ DBA/2. The effect was both gestational age-and dose-dependent. Gamma interferon and R-IL-2 enhanced resorptions from 38 to 68% and 76% respectively in the CBA/J \m=x\ DBA/2 mating combination, whereas the rates in CBA/J \m=x\ BALB/c matings were enhanced from 6 to 44% and 55%. Lipopolysaccharride (LPS), which is known to lead to the release of TNF-\g=a\, had a similar effect, leading to gestational age-and dose-dependent enhancement of resorptions up to 100%.However, cytokines of the CSF family, including IL-3 and GM-CSF, increased the chances of fetal survival when injected into abortion-prone mice, e.g. reducing resorption rates in the abortion-prone CBA/J \m=x\ DBA/2 mating combination from 55 to 22% (IL-3), and 47 to 8% (GM-CSF). They also increased fetal and placental weight and, in particular, expanded the spongiotrophoblast zone in the placenta. The latter observations may be due to a direct trophic influence on placental cells, perhaps through a cytokine cascade, or an indirect effect due to inhibition of natural killer (NK)-like cells, or both. Whatever the mechanism, these results may find practical application in influencing reproductive outcome in women and other species.

The embryo is most akin to a parasite, and pregnancy is most akin to a host-parasite interaction. If one excludes chromosome abnormalities in the embryo as a cause of death, activation of coagulation mechanisms, leading to vasculitis affecting the maternal blood supply to the implanted embryo, appears to represent a major loss-causing mechanisms--a form of ischemic autoamputation. Proinflammatory T-helper (Th) 1-type cytokines trigger this process via upregulation of a novel prothrombinase, fgl2. Th2/3 cytokines, such as interleukin (IL)-4, IL-10, and transforming growth factor (TGF)-beta 2, may antagonize the processes involved. Cytokine balance is determined by the genetics of the mother, which regulate her response to stress; endotoxin (LPS); and paternal antigens, selectively expressed on the trophoblast of the embryo, via imprinting. Based on studies in abortion-prone mice, where immunity to paternal alloantigens prevents loss, three distinct gene products in the embryo are proposed to determine the cytokine response to maternal lymphomyeloid cells in the uterus.

No abstract

During pregnancy, a local and systemic Th2 bias of maternal immunity favors Th1-dependent infections such as malaria. This study measured cytokines secreted in cultures of chorionic villi, placental blood cells (PBC), and serum in term placentas from 88 malaria-infected and -noninfected Cameroon women. Interleukin (IL)--2 and --4 were consistently low; IL-1 beta, IL-6, granulocyte-macrophage colony-stimulating factor, and transforming growth factor (TGF)--beta 2 were highest in villi cultures. Tumor necrosis factor (TNF)--alpha, interferon (IFN)--gamma, and IL-10 were highest in PBC cultures. Malaria placental infection increased Th1-type cytokines, whereas Th2-type cytokines and TGF-beta 2 were unchanged. Addition of lipopolysaccharide or infected erythrocytes to cultures increased TNF-alpha, IL-1 beta, IL-6, and IL-10 secretions but not those of IFN-gamma and IL-4. Overall, Plasmodium falciparum induced a placental immune response involving both Th1- and Th2-type cell activation. Although the Th1 pathway was favored, IL-10 secretion was also increased, and this increase should be effective in protecting the placenta by controlling the negative effects of Th1 cytokines on pregnancy.

Stress is known to induce abortions, but underlying mechanisms are unknown. Both alloimmunization and injection of antibody to the asialoGM1 determinant of natural killer cells have been shown to prevent stress-triggered abortion in mice. DBA/2J-mated CBA/J female mice were used to investigate the influence of stress during early gestation on systemic hormone levels and on cytokines in the decidua that are thought to be relevant to abortion in nonstress-related murine abortion. Lowered levels of progesterone did not occur as a result of stress. In stressed mice, increased levels of the abortogenic cytokine tumor necrosis factor alpha (TNF alpha) were associated with decreased levels of pregnancy-protective transforming growth factor beta 2-related suppressive activity in uterine decidua. In the alloimmunized animals where stress failed to boost the abortion rate, these effects were abrogated. Production of TNF alpha may be stimulated by the neurotransmitter substance P (SP); after injection of an SP receptor antagonist or SP-antibody, stress failed to increase the abortion rate above the background level. The increased levels of TNF alpha we observed in the stressed animals were completely abrogated in the animals that had received the SP receptor antagonist; stress also failed to decrease the pregnancy-protective suppressive activity in the decidua of these animals. The data indicate that stress may inhibit protective suppressor mechanisms and promote secretion of abortogenic cytokines such as TNF alpha via neurotransmitter SP.

Cytokines are indeed involved in implantation as they are in ongoing pregnancy and delivery. Relevance to infertility and recurrent pregnancy loss is discussed.

These data suggest that stress may inhibit protective suppressor mechanisms and promote secretion of abortogenic cytokines such as TNF-alpha. Possible mechanisms are discussed.

We conclude that the T helper cell type 1/2 (Th1/ Th2) paradigm, as useful as it has been to explain pregnancy, is no longer sufficient in view of the emerging complexity of the cytokine network at the materno-fetal interface. This is peculiarly true for implantation, which, as a step by step developmentally regulated process, involving inflammatory molecules, cannot fit into such a scheme.