Skip to main content

Advertisement

SpringerLink
Log in

Intrapituitary cytokines in Cushing’s disease: do they play a role?

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

A large body of in vitro evidence shows that cytokines influence the hypothalamic–pituitary–adrenal axis both in physiological conditions and in Cushing’s disease (CD). In order to study in vivo the role of intrapituitary cytokines in CD, we assayed two cytokines known for their action on the pituitary, i.e. interleukin-1 beta (IL-1β) and interleukin-6 (IL-6), and also soluble interleukin-6 receptor (sIL-6R), important for the neural activities of IL-6, in a carefully selected sample of subjects affected by CD undergoing bilateral inferior petrosal sinus sampling. Similarly to ACTH, all cytokines basally showed a higher concentration in the ipsilateral sinus compared to the controlateral one and to that of peripheral blood; after CRH infusion, both ipsilaterally and controlaterally, IL-6 and sIL-6R values increased compared to basal ones, while IL-1β increased significantly up to 5 min after CRH and then decreased significantly compared to basal values in subsequent measurements; peripherically no significant variations in the cytokines were observed after CRH. Again similarly to ACTH, the three cytokines presented a higher increase ipsilaterally than controlaterally; moreover all three interleukins in the ipsilateral sinuses showed positive and significant correlations between their basal value and that of basal ACTH. These findings allow us to hypothesize that the central production of IL-1β and IL-6 could be involved in ACTH hypersecretion which occurs in CD: more specifically, we hypothesize that these cytokines are produced directly by the corticotroph adenoma and have the task of enhancing tumoral secretion of ACTH with an autocrine-paracrine mechanism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Vilcek J, Feldmann M (2004) Historical review: cytokines as therapeutics and targets of therapeutics. Trends Pharmacol Sci 25:201–209. doi:10.1016/j.tips.2004.02.011

    Article  PubMed  CAS  Google Scholar 

  2. Oppenheim JJ (2001) Cytokines: past, present, and future. Int J Hematol 74:3–8. doi:10.1007/BF02982543

    Article  PubMed  CAS  Google Scholar 

  3. Haedo MR, Gerez J, Fuertes M, Giacomini D, Páez-Pereda M, Labeur M, Renner U, Stalla GK, Arzt E (2009) Regulation of pituitary function by cytokines. Horm Res 72:266–274. doi:10.1159/000245928

    Article  PubMed  CAS  Google Scholar 

  4. Cambronero JC, Rivas FJ, Borrell J, Guaza C (1992) Interleukin-1-beta induces pituitary adrenocorticotropin secretion: evidence for glucocorticoid modulation. Neuroendocrinology 55:648–654. doi:10.1159/000126184

    Article  PubMed  CAS  Google Scholar 

  5. Swolin-Eide D, Ohlsson C (1998) Effects of cortisol on the expression of interleukin-6 and interleukin-1 beta in human osteoblast-like cells. J Endocrinol 156:107–114. doi:10.1677/joe.0.1560107

    Article  PubMed  CAS  Google Scholar 

  6. Goujon E, Parnet P, Laye S, Combe C, Kelley KW, Dantzer R (1995) Stress downregulates lipopolysaccharide-induced expression of proinflammatory cytokines in the spleen, pituitary, and brain of mice. Brain Behav Immun 9:292–303. doi:10.1006/brbi.1995.1028

    Article  PubMed  CAS  Google Scholar 

  7. Del Rey A, Besedovsky H, Sorkin E, Dinarello CA (1987) Interleukin-1 and glucocorticoid hormones integrate an immunoregulatory feedback circuit. Ann N Y Acad Sci 496:85–90. doi:10.1111/j.1749-6632.1987.tb35749.x

    Article  PubMed  CAS  Google Scholar 

  8. Besedovsky H, del Rey A, Sorkin E, Dinarello CA (1986) Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 233:652–654. doi:10.1126/science.3014662

    Article  PubMed  CAS  Google Scholar 

  9. Renner U, De Santana EC, Gerez J, Fröhlich B, Haedo M, Pereda MP, Onofri C, Stalla GK, Arzt E (2009) Intrapituitary expression and regulation of the gp130 cytokine interleukin-6 and its implication in pituitary physiology and pathophysiology. Ann N Y Acad Sci 1153:89–97. doi:10.1111/j.1749-6632.2008.03970.x

    Article  PubMed  CAS  Google Scholar 

  10. Renner U, Gloddek J, Pereda MP, Arzt E, Stalla GK (1998) Regulation and role of intrapituitary IL-6 production by folliculostellate cells. Domest Anim Endocrinol 15:353–362. doi:10.1016/S0739-7240(98)00027-7

    Article  PubMed  CAS  Google Scholar 

  11. Hanisch A, Dieterich KD, Dietzmann K, Lüdecke K, Buchfelder M, Fahlbusch R, Lehnert H (2000) Expression of members of the interleukin-6 family of cytokines and their receptors in human pituitary and pituitary adenomas. J Clin Endocrinol Metab 85:4411–4414. doi:10.1210/jc.85.11.4411

    Article  PubMed  CAS  Google Scholar 

  12. McCann SM, Kimura M, Karanth S, Yu WH, Mastronardi CA, Rettori V (2000) The mechanism of action of cytokines to control the release of hypothalamic and pituitary hormones in infection. Ann NY Acad Sci 917:4–18. doi:10.1111/j.1749-6632.2000.tb05368.x

    Article  PubMed  CAS  Google Scholar 

  13. Brown SL, Smith LR, Blalock JE (1987) Interleukin 1 and interleukin 2 enhance proopiomelanocortin gene expression in pituitary cells. J Immunol 139:3181–3183

    PubMed  CAS  Google Scholar 

  14. De Souza EB (1993) Corticotropin-releasing factor and interleukin-1 receptors in the brain-endocrine-immune axis. Role in stress response and infection. Ann NY Acad Sci 697:9–27. doi:10.1111/j.1749-6632.1993.tb49919.x

    Article  PubMed  Google Scholar 

  15. Gloddek J, Pagotto U, Paez Pereda M, Arzt E, Stalla GK, Renner U (1999) 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. doi:10.1677/joe.0.1600483

    Article  PubMed  CAS  Google Scholar 

  16. Pereda MP, Lohrer P, Kovalovsky D, Perez Castro C, Goldberg V, Losa M, Chervín A, Berner S, Molina H, Stalla GK, Renner U, Arzt E (2000) Interleukin-6 is inhibited by glucocorticoids and stimulates ACTH secretion and POMC expression in human corticotroph pituitary adenomas. Exp Clin Endocrinol Diabetes 108:202–207. doi:10.1055/s-2000-7887

    Article  PubMed  CAS  Google Scholar 

  17. Malarkey WB, Zvara BJ (1989) Interleukin-1 beta and other cytokines stimulate adrenocorticotropin release from cultured pituitary cells of patients with Cushing’s disease. J Clin Endocrinol Metab 69:196–199. doi:10.1210/jcem-69-1-196

    Article  PubMed  CAS  Google Scholar 

  18. Watanobe H, Tamura T, Habu S, Kakizaki Y, Kohsaka A, Suda T (1998) Measurement of cytokines in the cavernous sinus plasma from patients with Cushing’s disease. Neuropeptides 32:119–123. doi:10.1016/S0143-4179(98)90026-9

    Article  PubMed  CAS  Google Scholar 

  19. Merola B, Longobardi S, Colao A, Di Somma C, Ferone D, Di Rella F, Pivonello R, Covelli V, Annunziato L, Lombardi G (1996) Tumor necrosis factor-alpha increases after corticotropin-releasing hormone administration in Cushing’s disease. In vivo and in vitro studies. Neuroendocrinology 64:393–397. doi:10.1159/000127142

    Article  PubMed  CAS  Google Scholar 

  20. Kurotani R, Yasuda M, Oyama K, Egashira N, Sugaya M, Teramoto A, Osamura RY (2001) Expression of interleukin-6, interleukin-6 receptor (gp80), and the receptor’s signal-transducing subunit (gp130) in human normal pituitary glands and pituitary adenomas. Mod Pathol 14:791–797

    Article  PubMed  CAS  Google Scholar 

  21. März P, Otten U, Rose-John S (1999) Neural activities of IL-6-type cytokines often depend on soluble cytokine receptors. J Neurosci 11:2995–3004. doi:10.1046/j.1460-9568.1999.00755.x

    Article  Google Scholar 

  22. Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, Fava GA, Findling JW, Gaillard RC, Grossman AB, Kola B, Lacroix A, Mancini T, Mantero F, Newell-Price J, Nieman LK, Sonino N, Vance ML, Giustina A, Boscaro M (2003) Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 88:5593–5602. doi:10.1210/jc.2003-030871

    Article  PubMed  CAS  Google Scholar 

  23. Oldfield EH, Doppman JL, Nieman LK, Chrousos GP, Miller DL, Katz DA, Cutler GB Jr, Loriaux DL (1991) Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N Engl J Med 325:897–905

    Article  PubMed  CAS  Google Scholar 

  24. Oldfield EH, Chrousos GP, Schulte HM, Schaaf M, McKeever PE, Krudy AG, Cutler GB Jr, Loriaux DL, Doppman JL (1985) Preoperative lateralization of ACTH-secreting pituitary microadenomas by bilateral and simultaneous inferior petrosal venous sinus sampling. N Engl J Med 312:100–103

    Article  PubMed  CAS  Google Scholar 

  25. Bonelli FS, Huston J 3rd, Carpenter PC, Erickson D, Young WF Jr, Meyer FB (2000) Adrenocorticotropic hormone-dependent Cushing’s syndrome: sensitivity and specificity of inferior petrosal sinus sampling. AJNR Am J Neuroradiol 21:690–696

    PubMed  CAS  Google Scholar 

  26. Holm S (1979) A Simple Sequentially Rejective Multiple Test Procedure. Scand J Stat 6:65–70

    Google Scholar 

  27. Courtois-Cox S, Jones SL, Cichowski K (2008) Many roads lead to oncogene-induced senescence. Oncogene 27:2801–2809. doi:10.1038/sj.onc.1210950

    Article  PubMed  CAS  Google Scholar 

  28. Leu SJ, Singh VK (1992) Stimulation of interleukin-6 production by corticotropin-releasing factor. Cell Immunol 143:220–227. doi:10.1016/0008-8749(92)90018-K

    Article  PubMed  CAS  Google Scholar 

  29. Singh VK, Leu SJ (1990) Enhancing effect of corticotropin-releasing neurohormone on the production of interleukin-1 and interleukin-2. Neurosci Lett 120:151–154. doi:10.1016/0304-3940(90)90025-5

    Article  PubMed  CAS  Google Scholar 

  30. Reyes TM, Coe CL (1998) Resistance of central nervous system interleukin-6 to glucocorticoid inhibition in monkeys. Am J Physiol 275:R612–R618

    PubMed  CAS  Google Scholar 

  31. DeRijk R, Michelson D, Karp B, Petrides J, Galliven E, Deuster P, Paciotti G, Gold PW, Sternberg EM (1997) Exercise and circadian rhythm-induced variations in plasma cortisol differentially regulate interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) production in humans: high sensitivity of TNF alpha and resistance of IL-6. J Clin Endocrinol Metab 82:2182–2191. doi:10.1210/jc.82.7.2182

    Article  PubMed  CAS  Google Scholar 

  32. Feldmann M (2008) Many cytokines are very useful therapeutic targets in disease. J Clin Invest 118:3533–3536. doi:10.1172/JCI37346

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

No external funding, apart from the support of the authors’ institutions, was available for this study.

Author information

Authors and Affiliations

  1. Department of Endocrinology and Diabetology, Cittadella, Italy

    Agostino Paoletta

  2. Division of Endocrinology, Department of Clinical Medicine and Applied Biotechnologies, Polytechnic University of Marche, Ospedali Riuniti, Via Conca 71, Torrette, 60020, Ancona, Italy

    Giorgio Arnaldi, Marco Boscaro & Giacomo Tirabassi

  3. Scientific-Technological Area, INRCA (Italian National Institute on Aging), Ancona, Italy

    Roberta Papa

Authors
  1. Agostino Paoletta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giorgio Arnaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roberta Papa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marco Boscaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Giacomo Tirabassi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marco Boscaro.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Paoletta, A., Arnaldi, G., Papa, R. et al. Intrapituitary cytokines in Cushing’s disease: do they play a role?. Pituitary 14, 236–241 (2011). https://doi.org/10.1007/s11102-010-0285-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-010-0285-9

Keywords

Search

Navigation