Chorionic gonadotropin induces dendritic cells to express a tolerogenic phenotype

Department of Immunology, Erasmus MC, Dr. Molewaterplein 50, NL-3015 GE Rotterdam, The Netherlands. .
Journal of Leukocyte Biology (Impact Factor: 4.29). 05/2008; 83(4):894-901. DOI: 10.1189/jlb.0407258
Source: PubMed


The pregnancy hormone human chorionic gonadotropin (hCG) has been suggested to play an immunoregulatory role in addition to its endocrine function, thus contributing to the prevention of fetal rejection. We hypothesized that hCG is involved in the maternal-fetal immune tolerance by the regulation of dendritic cell (DC) function. Therefore, we studied the effect of hCG on DC maturation. Upon hCG treatment in combination with LPS, mouse bone marrow-derived DC (BMDC) increased the ratio of IL-10:IL-12p70, down-regulated TNF-alpha, and decreased antigen-specific T cell proliferation. Addition of hCG together with LPS and IFN-gamma blocked MHC class II up-regulation, increased IL-10 production, and decreased the antigen-specific T cell proliferation by DC. Splenic DC showed similar results. Upon hCG treatment, IDO mRNA expression and its metabolite kynurenine were increased by LPS- and IFN-gamma-stimulated DC, suggesting its involvement in the decreased T cell proliferation. To study the effect of hCG on DC differentiation from precursors, BMDC were generated in the continuous presence of hCG. Under this condition, hCG decreased cytokine production and the induction of T cell proliferation. These data are suggestive for a contribution of hCG to the maternal-fetal tolerance during pregnancy by modifying DC toward a tolerogenic phenotype.

Download full-text


Available from: Durk Fekkes, Nov 18, 2014
12 Reads
  • Source
    • "This promotes clearance of apoptotic cells and defense against infections, two relevant mechanisms for pregnancy maintenance. hCG influences also dendritic cell differentiation and function, decreasing their ability to stimulate T cell proliferation (127). Finally, hCG has different effects on CD4+ T cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acceptance of the fetal semi-allograft by the mother's immune system has become the focus of intensive research. CD4+ T cells are important actors in the establishment of pregnancy. Th1/Th2 paradigm has been expanded to include CD4+ regulatory T (Treg) and T helper 17 (Th17) cells. Pregnancy hormones exert very significant modulatory properties on the maternal immune system. In this review, we describe mechanisms by which the endocrine milieu modulates CD4 T cell polarization during pregnancy. We first focused on Treg and Th17 cells and on their importance for pregnancy. Secondly, we review the effects of pregnancy hormones [progesterone (P4) and estradiol (E2)] on immune cells previously described, with a particular attention to human chorionic gonadotropin (hCG). The importance of Treg cells for pregnancy is evidenced. They are recruited before implantation and are essential for pregnancy maintenance. Decreased number or less efficient Treg cells are implicated in fertility disorders. As for Th17 cells, the few available studies suggest that they have a negative impact on fertility. Th17 frequency is increased in infertile patients. With the combination of its pro-effects on Th2 and Treg cells and anti-effects on Th1 and Th17 cells, P4 contributes to establishment of a favorable environment for pregnancy. E2 effects are more dependent on the context but it seems that E2 promotes Treg and Th2 cells while it inhibits Th1 cells. hCG positively influences activities of Treg and uterine natural killer cells. This embryo signal is an essential actor for the success of pregnancy, both as the endocrine factor regulating P4 secretion by the ovarian corpus luteum, but also as a paracrine agent during implantation as well as an angiogenic and immunologic mediator during the course of gestation. Luteinizing hormone (LH) immune properties begin to be studied but its positive impact on Treg cells suggests that LH could be a considerable immunomodulator in the mouse.
    Frontiers in Endocrinology 07/2014; 5:106. DOI:10.3389/fendo.2014.00106
  • Source
    • "Indoleamine 2,3-dioxygenase-1 can be induced by IFN-γ acting via Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, type I interferons, prostaglandin E2, lipopolysaccharide (LPS), DNA regions containing a high frequency of cytosine nucleotides adjacent to guanine nucleotides (CpG islands), and other factors in a variety of cell types such as DC, macrophages, epithelial and endothelial cells, Langerhans cells, astrocytes, and T lymphocytes. Also hormones such as estrogen (32) and human chorionic gonadotropin (hCG) (33–35) induce IDO1 expression. Upregulation of IDO1 in DC by hCG is independent of IFN-γ (34). "
    [Show abstract] [Hide abstract]
    ABSTRACT: This review discusses the mechanisms and consequences of degradation of tryptophan (Trp) in the placenta, focusing mainly on the role of indoleamine 2,3-dioxygenase-1 (IDO1), one of three enzymes catalyzing the first step of the kynurenine pathway of Trp degradation. IDO1 has been implicated in regulation of feto-maternal tolerance in the mouse. Local depletion of Trp and/or the presence of metabolites of the kynurenine pathway mediate immunoregulation and exert antimicrobial functions. In addition to the decidual glandular epithelium, IDO1 is localized in the vascular endothelium of the villous chorion and also in the endothelium of spiral arteries of the decidua. Possible consequences of IDO1-mediated catabolism of Trp in the endothelium encompass antimicrobial activity and immunosuppression, as well as relaxation of the placental vasotonus, thereby contributing to placental perfusion and growth of both placenta and fetus. It remains to be evaluated whether other enzymes mediating Trp oxidation, such as indoleamine 2,3-dioxygenase-2, Trp 2,3-dioxygenase, and Trp hydroxylase-1 are of relevance to the biology of the placenta.
    Frontiers in Immunology 05/2014; 5:230. DOI:10.3389/fimmu.2014.00230
  • Source
    • "This would imply that upon hormonal stimulation they acquire a rather pregnancy-friendly phenotype. The concrete impact of P4 on IL-10 secretion by activated rat and mouse BMDCs was differentially discussed and has to be further evaluated (101, 104, 105). In line with the hormonal-mediated induction of a tolerogenic phenotype in activated BMDCs, their T-cell stimulatory capacity was reduced. "
    [Show abstract] [Hide abstract]
    ABSTRACT: How the semi-allogeneic fetus is tolerated by the maternal immune system remains a fascinating phenomenon. Despite extensive research activity in this field the mechanisms underlying fetal tolerance are still not well understood. However, there are growing evidences that immune-immune interactions as well as immune-endocrine interactions build up a complex network of immune regulation that ensures fetal survival within the maternal uterus. In the present review, we aim to summarize emerging research data from our and other laboratories on immune modulating properties of pregnancy hormones with a special focus on progesterone, estradiol and human Chorionic Gonadotropin. These pregnancy hormones are critically involved in the successful establishment, maintenance and termination of pregnancy. They suppress detrimental maternal alloresponses while promoting tolerance pathways. This includes the reduction of the antigen-presenting capacity of dendritic cells, monocytes and macrophages as well as the blockage of natural killer cells, T and B cells. Pregnancy hormones also support the proliferation of pregnancy supporting uterine killer cells, retain tolerogenic dendritic cells and efficiently induce regulatory T cells. Furthermore, they are involved in the recruitment of mast cells and regulatory T cells into the fetal-maternal interface contributing to a local accumulation of pregnancy-protective cells. These findings highlight the importance of endocrine factors for the tolerance induction during pregnancy and encourage further research in the field.
    Frontiers in Immunology 04/2014; 5. DOI:10.3389/fimmu.2014.00196
Show more