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      Gender Differences and Hormonal Modulation of G Proteins Gα q/11 Expression in Lymphoid Organs

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          Abstract

          Androgens and estrogens exert potent divergent feedback effects on gonadotropin-releasing hormone (GnRH) production at the level of the hypothalamus and GnRH action at the level of the pituitary. Androgens exert generally suppressive effects on GnRH production and action, whereas rising levels of estradiol increase both GnRH release and action. In addition to its known endocrine actions, GnRH possesses immunomodulatory effects. We have previously demonstrated gender differences in immune responsiveness to GnRH that parallel gender differences in endocrine responsiveness: females appear to be more immunologically responsive to GnRH than males. GnRH exerts its actions via the stimulatory G protein Gα<sub>q</sub> and Gα<sub>11</sub> (referred to collectively as Gα<sub>q/11</sub>) as well as via Gα<sub>s</sub>. We have recently demonstrated that the heightened immune responsiveness to GnRH in lupus-prone female mice correlated with increased expression of Gα<sub>q/11</sub> in lymphoid cells from females compared to males. We hypothesize that the hormonal milieu of females may contribute to increased expression of stimulatory G proteins and to the heightened immune and endocrine responsiveness to GnRH. In this report, we document gender differences in expression of Gα<sub>q/11</sub> protein in lymphoid organs in non-autoimmune DBA/2 mice. In an effort to address the mechanisms for the gender differences in G-protein expression, we used competitive reverse transcription PCR to quantitate mRNA for stimulatory G proteins in immune cells under various hormonal conditions. We quantitated the expression of Gα<sub>q/11</sub> mRNA and protein under physiologic hormonal alterations, i.e. throughout the estrous cycle in female mice. We demonstrate that expression of Gα<sub>q/11</sub> mRNA and protein in lymphoid organs is significantly increased on the afternoon of proestrus compared to metestrus. Additional studies demonstrate that exposure to GnRH or to estrogens significantly increases the expression of Gα<sub>q/11</sub> mRNA in immune cells. These findings support an active role for hormonal modulation of G proteins in the gender differences in endocrinologic and immunologic responsiveness to GnRH.

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          Most cited references 5

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          Differential regulation of transforming growth factor beta and interleukin 2 genes in human T cells: demonstration by usage of novel competitor DNA constructs in the quantitative polymerase chain reaction

          The regulation of mRNA encoding transforming growth factor beta (TGF- beta) and interleukin 2 (IL-2) in normal human T cells was explored using novel competitor DNA constructs in the quantitative polymerase chain reaction and accessory cell-independent T cell activation models. Our experimental design revealed the following: (a) TGF-beta mRNA and IL-2 mRNA are regulated differentially in normal human T cells, quiescent or signaled with the synergistic combinations of: sn-1,2- dioctanoylglycerol and ionomycin or anti-CD3 monoclonal antibody (mAb) and anti-CD2 mAb; (b) the steady-state level of TGF-beta mRNA in the stimulated T cells, in contrast to that of IL-2 mRNA, is increased by the immunosuppressant cyclosporine (CsA); and (c) the paradoxical effect of CsA on TGF-beta mRNA levels is also appreciable at the level of production of functionally active TGF-beta protein. Our findings, in addition to demonstrating the utility of the competitor DNA constructs for the precise quantification of immunoregulatory cytokines, suggest a novel and unifying mechanistic basis for the immunosuppression and some of the complications (e.g., renal fibrosis) associated with CsA usage.
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            Cyclical Expression of GnRH and GnRH Receptor mRNA in Lymphoid Organs

            Gonadotropin-releasing hormone (GnRH) is known to possess dirct immunomodulatory effects. We have previously demonstrated that the administration of GnRH analogues modulates the expression of murine lupus independently of effects on gonadal steroids. We speculate that GnRH exerts direct actions at the level of the immune cells. GnRH receptors have been identified on lymphocytes. Because GnRH and GnRH receptor (GnRH-R) expression varies with the estrous cycle at the levels of the hypothalamus and pituitary, we speculated that similar cyclicity might be demonstrable in lymphoid tissue. In this report, we used competitive reverse transcription PCR to quantitate the expression of GnRH and GnRH-R mRNA in lymphoid organs throughout the estrous cycle in mice. We demonstrate that the pattern of expression of GnRH-R mRNA in spleen agrees closely with the pattern in the pituitaries of the same mice and the pattern previously reported in the rat pituitary, with significantly increased levels of expression seen on the afternoon of proestrus compared to the morning of metestrus. A similar pattern is seen with GnRH-R mRNA expression in the thymus. Furthermore, we show that the expression of GnRH mRNA in both thymus and spleen agrees closely with the pattern of expression of its receptor, with significantly increased levels of expression seen on the afternoon of proestrus compared to the morning of metestrus. Additional in vitro studies demonstrate that both GnRH and estradiol significantly increase the expression of GnRH-R mRNA in immune cells. These findings support an active role for GnRH in the immune system.
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              Activation of the progesterone receptor by the gonadotropin-releasing hormone self-priming signaling pathway

               J L Turgeon (1994)
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2003
                September 2003
                02 October 2003
                : 78
                : 3
                : 147-153
                Affiliations
                Section of Endocrinology, Children’s Mercy Hospital, Department of Pediatrics and Department of Pharmacy, University of Missouri-Kansas City School of Medicine, Kansas City, Mo., USA
                Article
                72796 Neuroendocrinology 2003;78:147–153
                10.1159/000072796
                14512707
                © 2003 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, References: 29, Pages: 7
                Categories
                Reproductive Neuroendocrinology

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