Download PDF
Exp Clin Endocrinol Diabetes 2004; 112(10): 587-594
DOI: 10.1055/s-2004-830404
Article

J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Expression of Gonadotropin-Releasing Hormone Type-I (GnRH-I) and Type-II (GnRH-II) in Human Peripheral Blood Mononuclear Cells (PMBCs) and Regulation of B-Lymphoblastoid Cell Proliferation by GnRH-I and GnRH-II

F. Tanriverdi1 , 2 , D. Gonzalez-Martinez2 , L. F. G. Silveira2 , Y. Hu2 , G. S. Maccoll2 , P. Travers3 , P. M. G. Bouloux2
  • 1Department of Endocrinology, Erciyes University Medical School, Talasyolu, Kayseri, Turkey
  • 2Department of Medicine, Neuroendocrine Unit, Royal Free and University College Medical School, London, UK
  • 3Immunology Unit, Royal Free and University College Medical School, London, UK
Further Information

Publication History

Received: October 23, 2003 First decision: December 15, 2003

Accepted: May 3, 2004

Publication Date:
02 December 2004 (online)

Also available at
    Permissions and Reprints

Abstract

GnRH-I and its receptor (GnRHR-I) have previously been demonstrated and shown to be biologically active in the immune system, notably within T cells. Recently however a second form of GnRH (GnRH-II) has been described in the human. The function of both these neuropeptides in B lymphocytes has not previously been explored. The present study investigates GnRH-I and GnRH-II expression in human peripheral mononuclear blood cells (PMBCs) and B lymphoblastoid cells (B-LCLs), as well as their action in regulating B-LCL proliferation in the presence and absence of interleukin-2 (IL-2), both in GnRHR-I mutated lymphocytes and in a normal control. RT-PCR and immunocytochemistry identified locally produced GnRH-I and GnRH-II in all cell groups. Treatment of normal B-LCLs with GnRH-I (10-9 M and 10-5 M) or with interleukin-2 (IL-2) (50 IU/ml) resulted in a significant increase in cell proliferation compared with the untreated control. IL-2 and GnRH-I (10-7 M, 10-6 M, 10-5 M) induced greater proliferation in normal B-LCLs than IL-2 treatment alone. No significant proliferation occurred in GnRHR-I defective B-LCLs, in response to either GnRH-I (10-9 and 10-5 M) or IL-2 treatment, nor to IL-2 and GnRH-I (10-10 to 10-5 M) co-treatment when compared to controls. Co-incubation of IL-2 and IL-2 + GnRH 10-5 M with a GnRH antagonist (Cetrorelix; 10-6 M) significantly attenuated the proliferation in normal B-LCLs. GnRH-II did not affect proliferation of normal B-LCLs alone, and did not alter the proliferative response to IL-2. Further investigation is required to clarify the physiological relevance of local GnRH-I/GnRH-II in immune system responsiveness.

Key words

GnRH-I - GnRH-II - B lymphocytes - proliferation - Interleukin-2

References

  • 1 Acien P, Quereda F J, Gomez-Torres M J, Bermejo R, Gutierrez M. GnRH analogues, transvaginal ultrasound-guided drainage and intracystic injection of recombinant interleukin-2 in the treatment of endometriosis.  Gynecol Obstet Invest. 2003;  55 96-104
    CrossrefPubMedSearch in Google Scholar
  • 2 Azad N, La Paglia N, Jurgens K A, Kirsteins L, Emanuele N V, Kelley M R, Lawrence A M, Mohagheghpour N. Immunoactivation enhances the concentration of luteinizing hormone-releasing hormone peptide and its gene expression in human peripheral T-lymphocytes.  Endocrinology. 1993;  133 215-223
    CrossrefPubMedSearch in Google Scholar
  • 3 Azad N, LaPaglia N, Kirsteins L, Uddin S, Steiner J, Williams D W, Lawrence A M, Emanuele N V. Jurkat cell proliferative activity is increased by luteinizing hormone-releasing hormone.  J Endocrinol. 1997;  153 241-249
    CrossrefPubMedSearch in Google Scholar
  • 4 Batticane N, Morale M C, Gallo F, Farinella Z, Marchetti B. Luteinizing hormone-releasing hormone signaling at the lymphocyte involves stimulation of interleukin-2 receptor expression.  Endocrinology. 1991;  129 277-286
    PubMedSearch in Google Scholar
  • 5 Chen A, Ganor Y, Rahimipour S, Ben Aroya N, Koch Y, Levite M. The neuropeptides GnRH-II and GnRH-I are produced by human T cells and trigger laminin receptor gene expression, adhesion, chemotaxis and homing to specific organs.  Nat Med. 2002;  8 1421-1426
    PubMedSearch in Google Scholar
  • 6 Chen A, Yahalom D, Laskar-Levy O, Rahimipour S, Ben Aroya N, Koch Y. Two isoforms of gonadotropin-releasing hormone are coexpressed in neuronal cell lines.  Endocrinology. 2001;  142 830-837
    CrossrefPubMedSearch in Google Scholar
  • 7 Chen H F, Jeung E B, Stephenson M, Leung P C. Human peripheral blood mononuclear cells express gonadotropin-releasing hormone (GnRH), GnRH receptor, and interleukin-2 receptor gamma-chain messenger ribonucleic acids that are regulated by GnRH in vitro.  J Clin Endocrinol Metab. 1999;  84 743-750
    CrossrefPubMedSearch in Google Scholar
  • 8 Conn P M, Crowley W F. Gonadotropin-releasing hormone and its analogues.  N Engl J Med. 1991;  324 93-103
    PubMedSearch in Google Scholar
  • 9 Davidson A, Diamond B. Autoimmune diseases.  N Engl J Med. 2001;  345 340-350
    CrossrefPubMedSearch in Google Scholar
  • 10 Dixit V D, Sridaran R, Edmonsond M A, Taub D, Thompson W E. Gonadotropin-releasing hormone attenuates pregnancy-associated thymic involution and modulates the expression of antiproliferative gene product prohibitin.  Endocrinology. 2003;  144 1496-1505
    CrossrefPubMedSearch in Google Scholar
  • 11 Gonzalez-Martinez D, Madigou T, Zmora N, Anglade I, Zanuy S, Zohar Y, Elizur A, Munoz-Cueto J A, Kah O. Differential expression of three different prepro-GnRH (gonadotrophin-releasing hormone) messengers in the brain of the european sea bass (Dicentrarchus labrax).  J Comp Neurol. 2001;  429 144-155
    PubMedSearch in Google Scholar
  • 12 Gould K G, Akinbami M A, Mann D R. Effect of neonatal treatment with a gonadotropin releasing hormone antagonist on developmental changes in circulating lymphocyte subsets: a longitudinal study in male rhesus monkeys.  Dev Comp Immunol. 1998;  22 457-467
    PubMedSearch in Google Scholar
  • 13 Jacobson J D, Ansari M A, Mansfield M E, McArthur C P, Clement L T. Gonadotropin-releasing hormone increases CD4 T-lymphocyte numbers in an animal model of immunodeficiency.  J Allergy Clin Immunol. 1999;  104 653-658
    PubMedSearch in Google Scholar
  • 14 Jacobson J D, Crofford L J, Sun L, Wilder R L. Cyclical expression of GnRH and GnRH receptor mRNA in lymphoid organs.  Neuroendocrinology. 1998;  67 117-125
    CrossrefPubMedSearch in Google Scholar
  • 15 Jacobson J D, Nisula B C, Steinberg A D. Modulation of the expression of murine lupus by gonadotropin-releasing hormone analogs.  Endocrinology. 1994;  134 2516-2523
    CrossrefPubMedSearch in Google Scholar
  • 16 Kakar S S, Musgrove L C, Devor D C, Sellers J C, Neill J D. Cloning, sequencing, and expression of human gonadotropin releasing hormone (GnRH) receptor.  Biochem Biophys Res Commun. 1992;  189 289-295
    CrossrefPubMedSearch in Google Scholar
  • 17 Kang S K, Tai C J, Nathwani P S, Leung P C. Differential regulation of two forms of gonadotropin-releasing hormone messenger ribonucleic acid in human granulosa-luteal cells.  Endocrinology. 2001;  142 182-192
    CrossrefPubMedSearch in Google Scholar
  • 18 Kasten T L, White S A, Norton T T, Bond C T, Adelman J P, Fernald R D. Characterization of two new preproGnRH mRNAs in the tree shrew: first direct evidence for mesencephalic GnRH gene expression in a placental mammal.  Gen Comp Endocrinol. 1996;  104 7-19
    CrossrefPubMedSearch in Google Scholar
  • 19 Kauffmann A S, Rissman E F. The evolutionarily conserved gonadotropin-releasing hormone II modifies food intake.  Endocrinology. 2004;  145 686-691
    PubMedSearch in Google Scholar
  • 20 Kim H J, Berek C. B cells in rheumatoid arthritis.  Arthritis Res. 2000;  2 126-131
    CrossrefPubMedSearch in Google Scholar
  • 21 Lipsky P E. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity.  Nat Immunol. 2001;  2 764-766
    CrossrefPubMedSearch in Google Scholar
  • 22 Mann D R, Howie S, Paulsen D F, Akinbami M A, Lunn S F, Fraser H M. Changes in lymphoid tissue after treatment with a gonadotropin releasing hormone antagonist in the neonatal marmoset (Callithrix jacchus).  Am J Reprod Immunol. 1998;  39 256-265
    PubMedSearch in Google Scholar
  • 23 Marchetti B, Guarcello V, Morale M C, Bartoloni G, Farinella Z, Cordaro S, Scapagnini U. Luteinizing hormone-releasing hormone-binding sites in the rat thymus: characteristics and biological function.  Endocrinology. 1989;  125 1025-1036
    PubMedSearch in Google Scholar
  • 24 Millar R, Conklin D, Lofton-Day C, Hutchinson E, Troskie B, Illing N, Sealfon S C, Hapgood J. A novel human GnRH receptor homolog gene: abundant and wide tissue distribution of the antisense transcript.  J Endocrinol. 1999;  162 117-126
    CrossrefPubMedSearch in Google Scholar
  • 25 Millar R, Lowe S, Conklin D, Pawson A, Maudsley S, Troskie B, Ott T, Millar M, Lincoln G, Sellar R, Faurholm B, Scobie G, Kuestner R, Terasawa E, Katz A. A novel mammalian receptor for the evolutionarily conserved type II GnRH.  Proc Natl Acad Sci USA. 2001;  98 9636-9641
    CrossrefPubMedSearch in Google Scholar
  • 26 Millar R P. GnRH II and type II GnRH receptors.  Trends Endocrinol Metab. 2003;  14 35-43
    PubMedSearch in Google Scholar
  • 27 Miyamoto K, Hasegawa Y, Nomura M, Igarashi M, Kangawa K, Matsuo H. Identification of the second gonadotropin-releasing hormone in chicken hypothalamus: evidence that gonadotropin secretion is probably controlled by two distinct gonadotropin-releasing hormones in avian species.  Proc Natl Acad Sci USA. 1984;  81 3874-3878
    CrossrefPubMedSearch in Google Scholar
  • 28 Morale M C, Batticane N, Bartoloni G, Guarcello V, Farinella Z, Galasso M G, Marchetti B. Blockade of central and peripheral luteinizing hormone-releasing hormone (LHRH) receptors in neonatal rats with a potent LHRH-antagonist inhibits the morphofunctional development of the thymus and maturation of the cell-mediated and humoral immune responses.  Endocrinology. 1991;  128 1073-1085
    PubMedSearch in Google Scholar
  • 29 Nilsson K. Human B-lymphoid cell lines.  Hum Cell. 1992;  5 25-41
    PubMedSearch in Google Scholar
  • 30 Schulz R W, Bosma P T, Zandbergen M A, Van der Sanden M C, Van Dijk W, Peute J, Bogerd J, Goos H J. Two gonadotropin-releasing hormones in the African catfish, Clarias gariepinus: localization, pituitary receptor binding, and gonadotropin release activity.  Endocrinology. 1993;  133 1569-1577
    CrossrefPubMedSearch in Google Scholar
  • 31 Sherwood N M, Lovejoy D A, Coe I R. Origin of mammalian gonadotropin-releasing hormones.  Endocr Rev. 1993;  14 241-254
    CrossrefPubMedSearch in Google Scholar
  • 32 Silveira L F, Stewart P M, Thomas M, Clark D A, Bouloux P M, MacColl G S. Novel Homozygous Splice Acceptor Site GnRH Receptor (GnRHR) Mutation: Human GnRHR “Knockout”.  J Clin Endocrinol Metab. 2002;  87 2973-2977
    CrossrefPubMedSearch in Google Scholar
  • 33 Standaert F E, Chew B P, De Avila D, Reeves J J. Presence of luteinizing hormone-releasing hormone binding sites in cultured porcine lymphocytes.  Biol Reprod. 1992;  46 997-1000
    PubMedSearch in Google Scholar
  • 34 Tanriverdi F, Silveira L F, MacColl G S, Bouloux P M. The hypothalamic-pituitary-gonadal axis: immune function and autoimmunity.  J Endocrinol. 2003;  176 293-304
    CrossrefPubMedSearch in Google Scholar
  • 35 White R B, Eisen J A, Kasten T L, Fernald R D. Second gene for gonadotropin-releasing hormone in humans.  Proc Natl Acad Sci USA. 1998;  95 305-309
    CrossrefPubMedSearch in Google Scholar
  • 36 Whitelaw P F, Eidne K A, Sellar R, Smyth C D, Hillier S G. Gonadotropin-releasing hormone receptor messenger ribonucleic acid expression in rat ovary.  Endocrinology. 1995;  136 172-179
    CrossrefPubMedSearch in Google Scholar
  • 37 Zakharova L A, Malyukova I V, Adamskaya E I, Kuznetsova T A, Shishkina I V. Luteinizing hormone-releasing hormone in thymus and hypothalamus of rat fetuses: suppressing effect of antagonist and of antibodies on concanavalin A-induced proliferation of thymocytes.  Biochemistry (Mosc). 2000;  65 1135-1139
    PubMedSearch in Google Scholar
  • 38 Zhou Z, Shackleton C H, Pahwa S, White P C, Speiser P W. Prominent sex steroid metabolism in human lymphocytes.  Mol Cell Endocrinol. 1998;  138 61-69
    CrossrefPubMedSearch in Google Scholar

Fatih Tanriverdi

Department of Endocrinology
Erciyes University Medical School

38039 Talasyolu, Kayseri

Turkey

Phone: + 903522338323

Fax: + 90 35 24 37 58 07

Email: fatihtan@erciyes.edu.tr