Exp Clin Endocrinol Diabetes 2000; Vol. 108(3): 202-207
DOI: 10.1055/s-2000-7887
Articles

© Johann Ambrosius Barth

Interleukin-6 is inhibited by glucocorticoids and stimulates ACTH secretion and POMC expression in human corticotroph pituitary adenomas[*]

M. Páez Pereda 1 , P. Lohrer 1 , D. Kovalovsky 2, 3 , C. Perez Castro 2 , V. Goldberg 4 , M. Losa 5 , A. Chervín 6 , S. Berner 6 , H. Molina 6, 7 , G. K. Stalla 1 , U. Renner 1 , E. Arzt 2, 3
  • 1 Max-Planck Institute of Psychiatry, Dept. of Endocrinology, Munich, Germany
  • 2 Laboratorio de Fisiologia y Biologia Molecular. Departamento de Biología, FCEN Universidad de Buenos Aires, Buenos Aires, Argentina
  • 3 Member of the Argentine National Research Council (CONICET)
  • 4 Instituto de Investigaciones Médicas, Facultad de Medicina. Universidad de Buenos Aires, Buenos Aires, Argentina
  • 5 Hospitale San Raffaele, Dept. of Neurosurgery, Milano, Italy
  • 6 Hospital Santa Lucía, Buenos Aires, Argentina
  • 7 Hospital Ramos Mejía, Buenos Aires, Argentina
Further Information

Publication History

Publication Date:
31 December 2000 (online)

Also available at
 

Summary:

Interleukins and their receptors are expressed intrinsically in the anterior pituitary and regulate hormone production and cell proliferation. It has previously been shown that interleukin-6 (IL-6) regulates hormone secretion in normal pituitary cells and cell lines. Here we examined the effects of IL-6 on propiomelanocortin (POMC) expression and ACTH production in corticotroph adenoma cells in vitro. We found that IL-6 stimulates both ACTH secretion and POMC gene expression in corticotroph adenoma cell cultures. This first demonstration of the stimulatory action of IL-6 on human corticotroph adenoma cell function provides further evidence for a direct action of IL-6 on corticotroph pituitary cells. We have confirmed previous reports of IL-6 production by corticotroph adenoma cells and in addition, demonstrated for the first time that the synthetic glucocorticoid dexamethasone is a potent suppressor of intratumoral IL-6 production. This intratumoral produced IL-6 may be in part responsible, in an autocrine manner, for the stimulation of ACTH synthesis and secretion. Our results suggest that IL-6 might play a role in the pathogenesis of Cushing's disease. However, elevated glucocorticoid levels in patients with Cushing's disease may prevent excessive action of IL-6 on ACTH production and tumor progression of corticotroph adenomas in vivo.

Key words:

Corticotroph adenoma - interleukin-6 - proopiomelanocortin - ACTH

1 * Supported by grants from the DFG: Sta 285/7-3, the Volkswagen Foundation (I/74 149), the University of Buenos Aires (UBA), the CONICET and Agencia Nacional de Promoción Científica y Tecnológica-Argentina. E.A. is a recipient of a fellowship of the John Simon Guggenheim Memorial Foundation.

References

  • 1 Allaerts W, Carmeliet P, Denef C. New perspectives in the function of pituitary folliculo-stellate cells.  Mol Cell Endocrinol.. 71 73-81 1990; 
    CrossrefPubMedGoogle Scholar
  • 2 Arzt E, Buric R, Stelzer G, Stalla J, Sauer J, Renner U, Stalla G K. Interleukin involvement in anterior pituitary cell growth regulation: effects of interleukin-2 and interleukin-6.  Endocrinology. 132 459-467 1993; 
    CrossrefPubMedGoogle Scholar
  • 3 Arzt E, Paez Pereda M, Perez Castro C, Pagotto U, Renner U, Stalla G K. Pathophysiological role of the cytokine network in the anterior pituitary gland.  Front Neuroendocrinol. 20 71-95 1999; 
    PubMedGoogle Scholar
  • 4 Arzt E, Stelzer G, Renner U, Lange M, Müller O A, Stalla G K. Interleukin-2 and interleukin-2 receptor expression in human corticotrophic adenoma and murine pituitary cell cultures.  J Clin Invest. 90 1944-1951 1992; 
    PubMedGoogle Scholar
  • 5 Besedovsky H, del Rey A. Immune-endocrine circuits: integrative role of cytokines.  Front Neuroendocrinol. 13 61-94 1992; 
    PubMedGoogle Scholar
  • 6 Carmeliet P, Vankelecom G, van Damme J, Billiau A, Denef C. Release of IL-6 from anterior pituitary cell aggregates: developmental pattern and modulation by glucocorticoids and forskolin.  Neuroendocrinology. 53 29-34 1991; 
    PubMedGoogle Scholar
  • 7 Farnoud M R, Kujas M, Derome P, Racadot J, Peillon F, Li J Y. Interactions between normal and tumoral tissues at the boundary of human pituitary adenomas.  Virchows Arch. 424 75-82 1994; 
    PubMedGoogle Scholar
  • 8 Fukata J, Usui T, Maitoh Y, Nakai Y, Imura H. Effects of recombinant human interleukin-1a, 1β and 6 on ACTH synthesis and release in the mouse pituitary tumor cell line AtT-20.  J Endocrinol. 122 33-39 1989; 
    PubMedGoogle Scholar
  • 9 Gloddek J, Pagotto U, Paez Pereda M, Arzt E, Stalla G K, Renner U. Pituitary adenylate cyclase-activating polypeptide, interleukin-6 and glucocorticoids regulate the release of vascular endothelial growth factor in pituitary folliculostellate cells.  J Endocrinol. 160 483-490 1999; 
    CrossrefPubMedGoogle Scholar
  • 10 Höfler H, Walter G F, Denk H. Immunohistochemistry of folliculo-stellate cells in normal human adenohypophyses and in pituitary adenomas.  Acta Neuropathol (Berl). 65 35-40 1984; 
    CrossrefPubMedGoogle Scholar
  • 11 Houssiau F A, Bukasa K, Sindic C JM, Van Damme J, Van Snick J. Elevated levels of the 26K human hybridoma growth factor (interleukin 6) in cerebrospinal fluid of patients with acute infection of the central nervous system.  Clin Exp Immunol. 71 320-327 1988; 
    PubMedGoogle Scholar
  • 12 Jonas T H, Daniels A, James R, Justice S, McCorkle R, Price A, Kendall-Taylor P, Weetman A. Production of bioactive and immunoreactive interleukin-6 and expression of IL-6 messenger RNA by human pituitary adenomas.  J Clin Endocrinol Metab. 78 180-187 1994; 
    CrossrefPubMedGoogle Scholar
  • 13 Jones T H, Justice S, Price A, Chapman K. IL-6 secreting human pituitary adenomas in vitro.  J Clin Endocrinol Metab. 73 207-209 1991; 
    PubMedGoogle Scholar
  • 14 Karl M, von Wichert G, Kempter E, Katz D A, Reincke M, Mönig H, Ali I U, Stratakis C A, Oldfield E H, Chrousos G P, Schulte H M. Nelson's syndrome associated with a somatic frame shift mutation in the glucocorticoid receptor gene.  J Clin Endocrinol Metab. 81 124-129 1996; 
    CrossrefPubMedGoogle Scholar
  • 15 Kobayashi H, Fukata J, Murakami B, Usui T, Ebisui O, Muro S, Hanaoka I, Inoue K, Imura H, Nakao K. TNF receptors in pituitary cells.  Brain Res. 758 45-50 1997; 
    CrossrefPubMedGoogle Scholar
  • 16 Koenig J I, Snow K, Clark B D, Toni R, Cannon J G, Shaw A R, Cinarello C A, Reichlin S, Lee S L, Lechan R M. Intrinsic pituitary interleukin-1ß is induced by bacterial lipopolysaccharide.  Endocrinology. 126 3053-3058 1990; 
    PubMedGoogle Scholar
  • 17 Lüdecke D K, Westphal M, Schabet M, Höllt V. In vitro secretion of ACTH, β-endorphin and β-lipotropin in Cushing's disease and Nelson's syndrome.  Horm Res. 13 259-279 1980; 
    PubMedGoogle Scholar
  • 18 Lyson K, McCann S. The effect of interleukin-6 on pituitary hormone release in vivo and in vitro.  Neuroendocrinology. 54 262-266 1991; 
    PubMedGoogle Scholar
  • 19 Malarkey W B, Zvara B J. Interleukin-1β and other cytokines stimulate adrenocorticotropin release from cultured pituitary cells of patients with Cushing's disease.  J Clin Endocrinol Metab. 69 196-199 1989; 
    PubMedGoogle Scholar
  • 20 Marin F, Kovacs K, Stefaneanu L, Horvath E, Cheng Z. S-100 protein immunopositivity in human nontumorous hypophyses and pituitary adenomas.  Endocr Pathol. 3 28-38 1992; 
    PubMedGoogle Scholar
  • 21 Matsumoto H, Koyama C, Sawada T, Koike K, Hirota K, Miyake A, Arimura A, Inoue K. Pituitary folliculo-stellate-like cell line (TtT/GF) responds to novel hypophysiotropic peptide (pituitary adenylate cyclase-activating polypeptide) showing increased adenosine 3′-5′-monophosphate and IL-6 secretion and cell proliferation.  Endocrinology. 133 2150-2155 1993; 
    CrossrefPubMedGoogle Scholar
  • 22 Naitoh Y, Fukata J, Tominaga T, Nakai Y, Tamai S, Mori K, Imura H. Interleukin-6 stimulates the secretion of adrenocorticotropic hormone in conscious, freely-moving rats.  Biochem Biophys Res Commun. 155 1459-1463 1988; 
    CrossrefPubMedGoogle Scholar
  • 23 Ohmichi M, Hirota K, Koike K, Kurachi K, Ohtsuka S, Matsusaki N, Yamaguchi M, Miyake A, Tanizawa O. Binding sites for interleukin-6 in the anterior pituitary gland.  Neuroendocrinology. 55 199-203 1992; 
    PubMedGoogle Scholar
  • 24 Páez Pereda M, Goldberg V, Chervín A, Carrizo G, Molina A, Andrada J, Sauer J, Renner U, Stalla G K, Arzt E. Interleukin2 (IL-2) and IL-6 regulate c-fos protooncogene expression in human pituitary adenoma explants.  Mol Cell Endocrinol. 124 33-42 1996; 
    CrossrefPubMedGoogle Scholar
  • 25 Renner U, Gloddek J, Arzt E, Inoue K, Stalla G K. Interleukin-6 is an autocrine growth factor for folliculostellate-like TtT/GF mouse pituitary tumor cells.  Exp Clin Endocrinol Diabetes. 105 345-352 1997; 
    PubMedGoogle Scholar
  • 26 Renner U, Gloddek J, Paez Pereda M, Arzt E, Stalla G K. Regulation and role of intrapituitary IL-6 production by folliculostellate cells.  Domest Anim Endocrinol. 15 353-362 1998; 
    CrossrefPubMedGoogle Scholar
  • 27 Renner U, Pagotto U, Arzt E, Stalla GK. Autocrine and paracrine roles of polypeptide growth factors, cytokines and vasogenic substances in normal and tumorous pituitary function and growth: a review.  Eur J Endocrinol. 135 515-532 1996; 
    PubMedGoogle Scholar
  • 28 Roberts J L, Seeburg P H, Shine J, Herbert E, Baxter J D, Goodman H M. Corticotrophin and β-endorphin: construction and analysis of recombinant DNA complementary to mRNA for the common precursor.  Proc Natl Acad Sci USA. 76 2153-2157 1979; 
    PubMedGoogle Scholar
  • 29 Sauer J, Renner U, Hopfner U, Lange M, Müller A, Strasburger C J, Pagotto U, Arzt E, Stalla G K. Interleukin-1β enhances interleukin-1 receptor antagonist content in human somatotroph adenoma cell cultures.  J Clin Endocrinol Metab. 83 2429-2434 1998; 
    CrossrefPubMedGoogle Scholar
  • 30 Sawada T, Koike K, Kanda Y, Ikesami H, Jikihara T, Maeda T, Osako Y, Hirota K, Miyake A. IL-6 stimulates cell proliferation of rat anterior pituitary clonal cell lines in vitro.  J Endocrinol Invest. 18 83-90 1995; 
    PubMedGoogle Scholar
  • 31 Spangelo B L, Isakson P C, MacLeod R M. Production of interleukin-6 by anterior pituitary cells is stimulated by increased intracellular adenosine 3′,5′-monophosphate and vasoactive intestinal peptide.  Endocrinology. 127 403-409 1990; 
    PubMedGoogle Scholar
  • 32 Spangelo B L, Jarvis W D, Judd A M, MacLeod R M. Induction of IL-6 release by IL-1 in rat anterior pituitary cells in vitro: evidence for an eicosanoid-dependent mechanism.  Endocrinology. 129 575-577 1991; 
    PubMedGoogle Scholar
  • 33 Spangelo B L, Gorospe W C. Role of the cytokines in the neuroendocrine-immune system axis.  Front Neuroendocrinol.. 16 1-22 1995; 
    PubMedGoogle Scholar
  • 34 Stalla G K, Brockmeier S J, Renner U, Newton C, Buchfelder M, Stalla J, Müller O A. Octreotide exerts different effects in vivo and in vitro in Cushing's disease.  Eur J Endocrinol. 130 125-131 1994; 
    PubMedGoogle Scholar
  • 35 Tatsuno I, Somogyvari-vigh A, Mizuno K, Gottschall P E, Hidaka H, Arimura A. Neuropeptide regulation of interleukin-6 production from the pituitary: stimulation by pituitary adenylate cyclase activating polypeptide and calcitonin gene-related peptide.  Endocrinology. 129 1797-1804 1991; 
    PubMedGoogle Scholar
  • 36 Tsagarakis S, Kontogeorgeos G, Giannou P, Thalassinos N, Woollley J, Besser G M, Grossman A. Interleukin-6, a growth promoting cytokine, is present in human pituitary adenomas: an immuno-cytochemical study.  Clin Endocrinol. 37 163-167 1992; 
    PubMedGoogle Scholar
  • 37 Ueta Y, Levy A, Chowdrey H S, Lightman S L. S-100 antigen-positive folliculostellate cells are not the source of IL-6 gene expression in human pituitary adenomas.  J Neuroendocrinol. 7 467-474 1995; 
    PubMedGoogle Scholar
  • 38 Vankelecom H, Carmeliet P, Van Damme J, Billau A, Denef C. Production of interleukin-6 by folliculo-stellate cells of the anterior pituitary gland in a histotipic cell aggregate culture system.  Neuroendocrinology. 49 102-106 1989; 
    PubMedGoogle Scholar
  • 39 Vankelecom H, Matthys P, Van Damme J, Heremans H, Biliau A, Denef C. Immuncytochemical evidence that S-100 positive cells of the mouse anterior pituitary contain IL-6 immunoreactivity.  J Histochem Cytochem. 41 151-156 1993; 
    PubMedGoogle Scholar
  • 40 Van Oers M HJ, van der Hyden A APAM, Aarden L A. Interleukin 6 (IL-6) in serum and urine of renal transplant recipients.  Clin Exp Immunol. 71 314-319 1988; 
    PubMedGoogle Scholar
  • 41 Velkeniers B, Vergani P, Trouillas J, D'Haens J, Hooghe R J, Hooghe-Peters E L. Expression of IL-6 mRNA in normal rat and human pituitaries and in human pituitary adenomas.  J Histochem Cytochem. 42 67-76 1994; 
    PubMedGoogle Scholar

1 * Supported by grants from the DFG: Sta 285/7-3, the Volkswagen Foundation (I/74 149), the University of Buenos Aires (UBA), the CONICET and Agencia Nacional de Promoción Científica y Tecnológica-Argentina. E.A. is a recipient of a fellowship of the John Simon Guggenheim Memorial Foundation.

Dr. Ulrich Renner

Max Planck Institute of Psychiatry

Dept. of Endocrinology

Kraepelinstr. 10

D-80804 Munich

Germany

Phone: ++ 49 89 30622 349

Fax: ++ 49 89 30622 605

Email: renner@mpipsykl.mpg.de

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