The Impact of Interleukin-10 in the Invasion Capacity and Immunoregulation During Pregnancy: the Implications of Pathogenesis of Pre-Eclampsia.

1. Pregnancy, pre-eclampsia and immune regulation The preeclampsia syndrome, which is characterized by changes in the placenta and uteroplacental vasculature, is a major concern in impaired human pregnancy. Hypertension, proteinuria and exaggerated edema are typical clinical symptoms1. Although the etiology of the disease is uncertain, it is well established that a defect in placental trophoblast invasion during implantation contributes to inadequate remodeling of uterine spiral arteries, thereby initiating focal regions of reduced perfusion within the placenta2. It has been suggested that a consequence of placental ischemia is the generation of cytotoxic factors that may act systemically to activate or injure the endothelium3. The identity of the factors elaborated by the placenta, which presumably compromise endothelial function during preeclampsia, is unknown. Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), are known to be potent activators of the vascular endothelium and have been proposed as mediators of endothelial dysfunction during preeclampsia4.

It is well known that the acceptance of the fetoplacental unit in human pregnancy requires maternal immune tolerance, which is thought to be regulated locally by the placenta. Therefore an anti-inflammatory cytokine, such as interleukin-10 plays a critical role in different pregnancy disorders, including preeclampsia5.

Placental interleukins have been identified in reproductive tissues, but their roles in adaptive maternal immunity and determining term pregnancy outcomes have not been fully clarified. The acceptance of the fetoplacental unit by the maternal uterine surface requires an element of immunological tolerance. Local antiplacental immunity is modified by synthesis of uncommon histocompatibility Ags, growth factors, and cytokines by the placenta. The presence of immune cells in the decidual tissue of the uterus also presents a potential barrier, both physical and immunological, to the development of the placenta6. Some characteristics of the fetoplacental unit encourage endometrial and myometrial invasion7 and others modify the immunological barrier (e.g. HLA-G)8. These characteristics of placental function may be abnormal at the formative stages of placental development, and thus the presumptive uterine barriers may be abnormal in preeclampsia, a complication of human pregnancy related to shallow placental development9. 2. Interleukin-10 Interleukin-10 was originally identified as the product of Th2-type T lymphocytes that inhibits the synthesis of Th-1 type cytokines such as Interferon-gamma and IL-210. IL-10 is known to be secreted by Th2-helper T cells, CD4+HT2 cells, and some B cell lymphoma and mast cell lines. The protein undergoes post-translational modification that includes N-glycosylation and the formation of critical cysteine bonds. IL-10 inhibits cytokine synthesis in both T cells and NK cells by controlling macrophage-monocyte accessory cells. IL-10 elicits responses in granulocytes, eosinophils, mast cells, B cells, T cells and NK cells11. IL-10 is crucial in limiting inflammatory responses in some disease states. The ability of IL-10 to inhibit macrophage activation should allow investigation into "cross-talk" between stimulatory and inhibitory cytokines. IL-10 is important in understanding autoimmunity and as a target molecule in the development of anti-rejection therapies12. The Th-like responses of this cytokine make it a suitable adjuvant for immunization development10.

Human and mouse IL-10 are 73% homologous at the amino acid level. Human IL-10 is active in mouse cell lines, but human cell lines are not responsive to mouse IL-10. 3. Maintenance of pregnancy and interleukin-10 production Interleukin-10 (IL-10) is an immunosuppressive cytokine expressed throughout pregnancy by epithelial cells and leukocytes in the endometrium and placenta. The anti-inflammatory and immune deviating properties of IL-10 are well characterized. Principally these are mediated through inhibiting proliferation and pro-inflammatory cytokine synthesis in type 1 T helper (Th1) cells, programming specific phenotypes in macrophages and dendritic cells and stimulating natural killer (NK) cell activation.

IL-10 has been shown in normal placental cells (trophoblast cells) to suppress the mixed lymphocyte responses in vitro13. Maternal bone marrow-derived cells in the uterine wall include NK-like cells and T cells14 that may be modified by placental IL-10 production. Modification of the local maternal antifetal immune response has been shown to be important in patients with recurrent spontaneous abortion15.