Estrogen and progesterone regulate the IL-6 signal transduction pathway in antibody secreting cells
Instituto de Estudios de la Inmunidad Humoral Profesor Ricardo A. Margni (IDEHU), Consejo Nacional de Investigaciones Científicas y Tecnológicas, Universidad de Buenos Aires, Junín 956, 4to piso (1113), Buenos Aires, Argentina.The Journal of Steroid Biochemistry and Molecular Biology (Impact Factor: 3.63). 06/2008; 111(3-5):255-61. DOI: 10.1016/j.jsbmb.2008.06.009
Regulation of the immune response is necessary to allow successful pregnancy. Asymmetric IgG antibodies are involved in fetal maintenance. We have previously demonstrated that estrogen (E2) and progesterone (P4) modulate the synthesis of asymmetric antibodies but the underlying mechanisms remain unclear. Since IL-6 and a progesterone-induced blocking factor (PIBF) were shown to regulate asymmetric antibody synthesis, in this work we analyzed whether E2 and P4 were able to modulate IL-6 signal transduction pathways and the ability of P4 to induce PIBF synthesis, in hybridoma B cells was also evaluated. We found that the IL-6 treatment induced an increase in the expression of gp130 and JAK1 by the hybridoma. E2 and P4 diminished the IL-6-induced gp130 expression in a dose-dependent manner, whereas the expression of JAK1 was not significantly affected. At 10(-6)M concentration, the steroids inhibited the phosphorylation of gp130 and diminished the IL-6-induced STAT3 phosphorylation and translocation to the nucleus. Maximal PIBF expression was observed when the hybridoma was cultured with 10(-10)M P4, compared to the control (p<0.05). Results demonstrate two molecular mechanisms, the modulation of the IL-6R signal transduction pathway and PIBF induction, which could be involved in the immunoregulatory role of sexual steroids during pregnancy.
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ABSTRACT: We propose a statistical method for uncovering gene pathways that characterize cancer heterogeneity. To incorporate knowledge of the pathways into the model, we define a set of activities of pathways from microarray gene expression data based on the sparse probabilistic principal component analysis. A pathway activity logistic regression model is then formulated for cancer phenotype. To select pathway activities related to binary cancer phenotypes, we use the elastic net for the parameter estimation and derive a model selection criterion for selecting tuning parameters included in the model estimation. Our proposed method can also reverse-engineer gene networks based on the identified multiple pathways that enables us to discover novel gene-gene associations relating with the cancer phenotypes. We illustrate the whole process of the proposed method through the analysis of breast cancer gene expression data.2010 IEEE International Conference on Bioinformatics and Biomedicine, BIBM 2010, Hong Kong, China, 18 - 21 December 2010, Proceedings; 01/2010
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ABSTRACT: The sex hormones that play major roles in the neuroimmune regulatory network include gonadotropins, prolactin, estrogens, progestogens, androgens and their agonists and antagonists. The steroid hormones listed above have membrane and cytoplasmic or nuclear receptors. Nuclear receptors are transcription factors that directly regulate gene expression. Luteinizing hormone releasing hormone and gonadotropins exert a direct regulatory influence on the immune system, in addition to the regulation of sex steroid hormones. In turn immune-derived cytokines regulate the production of gonadotropins. These mechanisms insure the coordination of reproduction with health status and prevent inopportune conception. Prolactin maintains adaptive immunocompetence and is a powerful stimulant of adaptive immune reactions. It plays a role in autoimmune disease, hematopoiesis and in host resistance to infectious disease. Estrogens regulate the thymus and suppress cell-mediated immune reactions. The antibody response and natural immunity (NK cytotoxicity, phagocytosis) are augmented by estradiol. Testosterone is immunosuppressive during trauma and shock. Many of the immunological effects of testosterone are due to its conversion to estradiol by aromatase in the thymus and in other lymphoid organs. The adrenal androgen, dehydroepiandrosterone stimulates immune reactions in experimental animals and in man. It antagonizes the immunosuppressive effect of glucocorticoids and its age-related decline may contribute to the immunodeficiency that develops in elderly individuals. Progesterone is a powerful immunosuppressive hormone. It plays a major role in the protection of the foetus during mammalian reproduction. Progesterone also contributes to the generation of self tolerance and protects against the excessive activation of the immune system. In this article the above listed hormones, their agonists and antagonists are discussed from the point of view of treating human diseases. By now autoimmune disease and cancer are routinely treated with sex hormones and their analogues. Additional opportunities may open up in infectious disease and in parasitic infestations.Immunology Endocrine & Metabolic Agents - Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology Endocrine & Metabolic Agents) 01/2010; 10(3):142-181.
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ABSTRACT: Progesterone (P4) plays different physiological roles, including reproductive and non-reproductive actions. Most of P4 effects are mediated by its interaction with its nuclear receptor (PR). Among the non-reproductive functions of P4, the regulation of the immune response, particularly during pregnancy, is remarkably important. P4 is able to modulate the immune response during normal physiological processes, as well as in infectious diseases, including parasitic and viral infections. During parasitic infections, P4 not only exerts its action upon the immune system, but also directly acts on the parasite, as it has been shown for helminthes and protozoans. Variations of P4 levels during the menstrual cycle could be involved in changes in susceptibility to infection, such as that caused by the human immunodeficiency virus (HIV). P4 could be involved in the acquisition and development of HIV disease, regulating infection susceptibility. Further investi-gations could open new application fields, where the differential effects of P4 upon the immune response represent the keystone of a successful hormonal therapy as well as the design of new drugs with more specific actions on parasites and virus.The Open Neuroendocrinology Journal 01/2010; 3:137-142.
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