Download PDF
Exp Clin Endocrinol Diabetes 2006; 114(1): 6-10
DOI: 10.1055/s-2005-873007
Article

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

Expression of the Glucocorticoid Receptor in the Human Adrenal Cortex

H.-J. Paust1 , S. Loeper1 , T. Else1 , 3 , A.-M. Bamberger2 , G. Papadopoulos1 , D. Pankoke1 , W. Saeger4 , C. M. Bamberger1
  • 1Center of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 2Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 3Division of Endocrinology and Metabolism, Dept. of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
  • 4Institute of Pathology, Marienkrankenhaus Hamburg, Germany
Further Information

Publication History

Received: March 10, 2005 First decision: July 10, 2005

Accepted: October 28, 2005

Publication Date:
01 February 2006 (online)

Also available at
    Permissions and Reprints

Abstract

Glucocorticoids produced in the adrenal cortex act by binding to a specific intracellular protein, the glucocorticoid receptor (GR), which then modulates gene transcription in target tissues. Whether the adrenal cortex itself is a glucocorticoid target tissue has not been analyzed as yet. Since the presence of GR would be a prerequisite for such “intracortical” glucocorticoid action, this study was designed to analyze GR expression in the normal human adrenal gland using RT‐PCR, Western blot, and immunohistochemistry. RT‐PCR revealed the presence of GR mRNA in adrenal cortex as well as in NCIh295 cells. These results were confirmed at the protein level by Western blot employing a specific anti-human GR antibody. Immunohistochemically, weak GR staining was observed in the adrenal medulla. In contrast, GR was strongly expressed in the adrenal cortex with the zona reticularis showing the most intense staining. Transfection of a GR-responsive luciferase reporter gene into NCIh295 cells resulted in dexamethasone-dependent induction of luciferase activity, indicating that GR is functional in this tissue. In this study, we show for the first time that GR is expressed in the human adrenal cortex. Its preferential expression in the zona reticularis may indicate a functional role in the regulation of adrenal androgen biosynthesis.

Key words

Glucocorticoid receptor - adrenal cortex

References

  • 1 Akner G, Wikstrom A C, Gustafsson J A. Subcellular distribution of the glucocorticoid receptor and evidence for its association with microtubules.  J Steroid Biochem Mol Biol. 1995;  52 1-16
    CrossrefPubMedGoogle Scholar
  • 2 Alesci S, Bornstein S R. Intraadrenal mechanisms of DHEA regulation: a hypothesis for adrenopause.  Exp Clin Endocrinol Diabet. 2001;  109 75-82
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Bamberger C M, Bamberger A M, de Castro M, Chrousos G P. Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans.  J Clin Invest. 1995;  95 2435-2441
    PubMedGoogle Scholar
  • 4 Bamberger C M, Schulte H M, Chrousos G P. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids.  Endocr Rev. 1996;  17 245-261
    CrossrefPubMedGoogle Scholar
  • 5 Bourdeau I, Lacroix A, Schurch W, Caron P, Antakly T, Stratakis C A. Primary pigmented nodular adrenocortical disease: paradoxical responses of cortisol secretion to dexamethasone occur in vitro and are associated with increased expression of the glucocorticoid receptor.  J Clin Endocrinol Metab. 2003;  88 3931-3937
    CrossrefPubMedGoogle Scholar
  • 6 Burnstein K L, Bellingham D L, Jewell C M, Powell-Oliver F E, Cidlowski J A. Autoregulation of glucocorticoid receptor gene expression.  Steroids. 1991;  56 52-58
    CrossrefPubMedGoogle Scholar
  • 7 Burnstein K L, Jewell C M, Cidlowski J A. Human glucocorticoid receptor cDNA contains sequences sufficient for receptor down-regulation.  J Biol Chem. 1990;  265 7284-7291
    PubMedGoogle Scholar
  • 8 Ceccatelli S, Dagerlind A, Schalling M, Wistrom A C, Okret S, Gustafsson J A, Goldstein M, Hokfelt T. The glucocorticoid receptor in the adrenal gland is localized in the cytoplasm of adrenaline cells.  Acta Physiol Scand. 1989;  137 559-560
    PubMedGoogle Scholar
  • 9 Chrousos G P. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation.  N Engl J Med. 1995;  332 1351-1362
    CrossrefPubMedGoogle Scholar
  • 10 Cole T J, Blendy J A, Monaghan A P, Krieglstein K, Schmid W, Aguzzi A, Fantuzzi G, Hummler E, Unsicker K, Schutz G. Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation.  Genes Dev. 1995;  9 1608-1621
    CrossrefPubMedGoogle Scholar
  • 11 Condon J, Gosden C, Gardener D, Nickson P, Hewison M, Howie A J, Stewart P M. Expression of type 2 11beta-hydroxysteroid dehydrogenase and corticosteroid hormone receptors in early human fetal life.  J Clin Endocrinol Metab. 1998;  83 4490-4497
    CrossrefPubMedGoogle Scholar
  • 12 De Bosscher K, Vanden Berghe W, Haegeman G. The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: molecular mechanisms for gene repression.  Endocr Rev. 2003;  24 488-522
    CrossrefPubMedGoogle Scholar
  • 13 Dickerman Z, Grant D R, Faiman C, Winter J S. Intraadrenal steroid concentrations in man: zonal differences and developmental changes.  J Clin Endocrinol Metab. 1984;  59 1031-1036
    PubMedGoogle Scholar
  • 14 Ehrhart-Bornstein M, Hinson J P, Bornstein S R, Scherbaum W A, Vinson G P. Intraadrenal interactions in the regulation of adrenocortical steroidogenesis.  Endocr Rev. 1998;  19 101-143
    CrossrefPubMedGoogle Scholar
  • 15 Hermann M A, Schulz C A, Claude P. Effects of NGF and glucocorticoid on NGF receptor immunolabeling of cultured rhesus adrenal chromaffin cells.  Exp Cell Res. 1992;  200 370-378
    CrossrefPubMedGoogle Scholar
  • 16 Hollenberg S M, Weinberger C, Ong E S, Cerelli G, Oro A, Lebo R, Thompson E B, Rosenfeld M G, Evans R M. Primary structure and expression of a functional human glucocorticoid receptor cDNA.  Nature. 1985;  318 635-641
    CrossrefPubMedGoogle Scholar
  • 17 Innouye K E, Chan O, Yue J TY, Matthews S G, Vranic M. Effects of diabetes and recurrent hypoglycemia on the regulation of the sympathoadrenal system and hypothalamo-pituitary-adrenal axis.  Am J Physiol Endocrinol Metab. 2005;  288 E422-E429
    CrossrefPubMedGoogle Scholar
  • 18 Jenkins B D, Pullen C B, Darimont B D. Novel glucocorticoid receptor coactivator effector mechanisms.  Trends Endocrinol Metab. 2001;  12 122-126
    PubMedGoogle Scholar
  • 19 Judd A M, Call G B, Barney M, McIlmoil C J, Balls A G, Adams A, Oliveira G K. Possible function of IL‐6 and TNF as intraadrenal factors in the regulation of adrenal steroid secretion.  Ann NY Acad Sci. 2000;  917 628-637
    PubMedGoogle Scholar
  • 20 Kontula K, Pomoell U M, Gunsalus G L, Pelkonen R. Glucocorticoid receptors and responsiveness of normal and neoplastic human adrenal cortex.  J Clin Endocrinol Metab. 1985;  60 283-289
    PubMedGoogle Scholar
  • 21 Lai G J, McCobb D P. Opposing actions of adrenal androgens and glucocorticoids on alternative splicing of Slo potassium channels in bovine chromaffin cells.  Proc Natl Acad Sci USA. 2002;  99 7722-7727
    CrossrefPubMedGoogle Scholar
  • 22 Mangelsdorf D J, Thummel C, Beato M, Herrlich P, Schütz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans R M. The nuclear receptor superfamily: the second decade.  Cell. 1995;  83 835-839
    CrossrefPubMedGoogle Scholar
  • 23 Nawata H, Yanase T, Higuchi K, Kato K, Ibayashi H. Epinephrine and norepinephrine synthesis are regulated by a glucocorticoid receptor-mediated mechanism in the bovine adrenal medulla.  Life Sci. 1985;  36 1957-1966
    CrossrefPubMedGoogle Scholar
  • 24 Oakley R H, Sar M, Cidlowski J A. The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function.  J Biol Chem. 1996;  271 9550-9559
    CrossrefPubMedGoogle Scholar
  • 25 Schaaf M J, Cidlowski J A. Molecular Mechanisms of glucocorticoid action and resistance.  J Steroid Biochem Mol Biol. 2002;  83 37-48
    CrossrefPubMedGoogle Scholar
  • 26 Silva C M, Powell-Oliver F E, Jewell C M, Sar M, Allgood V E, Cidlowski J A. Regulation of the human glucocorticoid receptor by long-term and chronic treatment with glucocorticoid.  Steroids. 1994;  59 436-442
    CrossrefPubMedGoogle Scholar
  • 27 Truss M, Beato M. Steroid hormone receptors: interaction with deoxyribonucleic acid and transcription factors.  Endocr Rev. 1993;  14 459-479
    CrossrefPubMedGoogle Scholar
  • 28 Tsai M ‐J, O'Malley B W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members.  Ann Rev Biochem. 1994;  63 451-486
    CrossrefPubMedGoogle Scholar
  • 29 Yang G, Matocha M F, Rapoport S I. Increased numbers of extra-adrenal chromaffin cells in the abdominal paraganglia of senescent F344 rats: a possible role for the glucocorticoid receptor.  Cell Tissue Res. 1990;  259 233-238
    PubMedGoogle Scholar

M.D., Professor of Medicine and Endocrinology Christoph M. Bamberger

Center of Internal Medicine
University Hospital Hamburg-Eppendorf

Martinistr. 52

20246 Hamburg, Germany

Phone: + 4940428033907

Fax: + 49 4 04 28 03 92 52

Email: bamberger@uke.uni-hamburg.de

      >