Thymic Peptides: Transmitters Between the Neuroendocrine and the Immune System

  • Mireille Dardenne
  • Bared Safieh-Garabedian
  • Jean-Marie Pleau

Abstract

Synthesized within the thymus, thymic peptides comprise a heterogenous family of polypeptidic hormones, that exerts important regulatory effects within the immune and the neuroendocrine systems. These peptides are themselves subject to control by hormones derived from the hypothalamo-pituitary axis and other endocrine glands. Regarding thymic hormonal function, thymulin production is upregulated by several hormones, including prolactin, growth hormone and thyroid hormones. Other aspects of thymic epithelial cell (’l’EC) physiology can also be modulated by hormones and neuropeptides, particularly cytokeratin expression, cell growth and production of extracellular matrix proteins, thus characterizing the pleiotropic action of these molecules on the thymic epithelium. Conversely, thymic derived peptides also regulate hormone release from the hypothalamo-pituitary axis and may act directly on target endocrine glands of this axis, modulating gonadal tissues. In addition, it has recently been shown that thymulin can modulate some peripheral nervous sensory functions, including those related to sensitivity to pain. According to the dose given, thymulin induces or reduces hyperalgesia related to both mechanical and thermal nociceptors and thus represents an important interface between the immune, endocrine and nervous systems.

Key words

Thymus Thymic epithelial cells Thymic peptides Thymulin Pituitary hormones Pain 

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References

  1. Angioni, S., Iori, G., Cellini, M., Sardelli, S., Massolo, F., Petraglia, F. and Genazzani, A.R., Acute beta-interferon or thymopentin administration increases plasma growth hormone and cortisol levels in children, Acta Endocrinol., 127 (1992) 237–241.PubMedGoogle Scholar
  2. Bach, J.F., Thymulin (FTS-Zn), Clin. Immunol. & Allergy, 3 (1983) 133–156.Google Scholar
  3. Badamchian, M., Spangelo, B.L., Damavandy, T., Mac Leod, R.M. and Goldstein, A.L., Complete amino acid sequence analysis of a peptide isolated from the thymus that enhances release of growth hormone and prolactin, Endocrinology, 128 (1991) 1580–1588.PubMedCrossRefGoogle Scholar
  4. Blalock, J.E., Production of peptide hormones and neurotransmitters by the immune system. In: J.E. Blalock (Eds.), Neuroimmunoendocrinology, 52, Karger, Basel, 1992, pp. 1–195.CrossRefGoogle Scholar
  5. Brown, O.A., Sosa, Y.E., Dardenne, M., Pleau, J.M. and Goya, R.G., Growth hormone-releasing activity of thymulin on pituitary somatotropes is age dependant, Neuroendocrinology, 69 (1999) 20–27.PubMedCrossRefGoogle Scholar
  6. Buckingham, J.C., Safieh, B., Singh, S. and Kendall, M.D., Interactions of corticotrophin and glucocorticoids in the control of thymulin release in the rat, Br. J. Pharmacol., 102 (1991) 15P.Google Scholar
  7. Buckingham, J.C., Safieh-Garabedian, B., Singh, S., Arduino, L.A., Cover, P.O. and Kendall, M.D., Interactions between the hypothalamus-pituitary adrenal axis and the thymus in the rat: a role for corticotrophin in the control of thymulin release, J. Neuroendocrinol., 4 (1992) 295–301.PubMedCrossRefGoogle Scholar
  8. Dardenne, M. and Savino, W., Neuroendocrine control of thymic epithelium: Modulation of thymic endocrine function, cytokeratin expression, and cell proliferation by hormones and neuropeptides, Prog. Neuroendocrinimmunol, 3 (1990) 18–25.Google Scholar
  9. Dardenne, M. and Savino, W., Control of thymus physiology by peptidic hormones and neuropeptides, Immunol. Today, 15 (1994) 518–523.PubMedCrossRefGoogle Scholar
  10. Dardenne, M., Savino, W., Gagnerault, M.C., Itoh, T. and Bach, J.F., Neuroendocrine control of thymic hormonal production. I. Prolctin stimulates in vivo and in vitro the production of thymulin by human and murine thymic epithelial cells, Endocrinology, 125 (1989) 3–12.PubMedCrossRefGoogle Scholar
  11. Fabris, N., Mocchegiani, E., Mariotti, S., Pacini, F. and Pinchera, A., Thyroid function modulates thymic endocrine activity, J. Clin. Endocrin. Metab., 75 (1986) 1251–1260.Google Scholar
  12. Farah, J.M., Hall, N.R., Bishop, J. F., Goldstein, A.L. and O’Donohue, T.L., Thymosin fraction 5 stimulates secretion of immunoreactive beta-endorphin in mouse tumor cells, J. Neurosci. Res., 18 (1987) 140–146.PubMedCrossRefGoogle Scholar
  13. Goldstein, G. and Audhya, T., Thymopoietin to thymopentin experimental studies. In: E. Sundal (Ed.), Thymopentin experimental and clinical medicine, Karger, Basel, 1985, pp. 1–21.Google Scholar
  14. Goya, R.G., Sosa, Y.E., Quigley, K.L., Gottschall, P.E., Goldstein, A.L. and Meites, J., Differential activity of thymosin peptides (thymosin fraction five) on plasma thyrotropin in female rats of different ages, Neuroendocrinology, 47 (1988) 379–383.PubMedCrossRefGoogle Scholar
  15. Goya, R.G., Takahashi, S., Quigley, K.L., Sosa, Y.E., Goldstein, A.L. and Meites, J., Immuneneuroendocrine interactions during aging: age-dependent thyrotropin-inhibiting activity of thymosin peptides, Mech. Ageing Dev., 41 (1987) 219–227.PubMedCrossRefGoogle Scholar
  16. Goya, R.G., Sosa, Y.E., Quigley, K.L., Reichhart, R. and Meites, J., Homeostatic thymus hormone stimulates corticosterone secretion in a dose-and age-dependent manner in rats, Neuroendocrinology, 51 (1990) 59–63.PubMedCrossRefGoogle Scholar
  17. Goya, R.G., Quigley, K.L., Takahashi, S., Reichhart, R. and Meites, J., Differential effect of homeostatic thymus hormone on plasma thyrotropin and growth hormone in young and old rats, Mech. Ageing Dev., 49 (1989) 119–128.PubMedCrossRefGoogle Scholar
  18. Hadley, A.J., Rantle, C.M. and Buckingham, J.C., Thymulin stimulates corticotrophin release and cyclic nucleotide formation in the rat anterior pituitary gland, NeuroImmunoModulation, 4 (1997) 62–69.PubMedGoogle Scholar
  19. Hall, J.R., McGillis, J.P., Spangelo, B.L., Palaszynzki, E., Moody, T. and Goldstein, AL., Evidence for a neuroendocrine-thymus axis mediated by thymosin polypeptides. In: B. Serrou, C. Rosenfeld, J.C. Daniels J.P. Saunders (Eds.), Current Concepts in Human Immunology and Cancer Immunomodulation, 17, Elsevier, Amsterdam, 1982, pp. 653–660.Google Scholar
  20. Healy, D.L., Hodgen, G.D., Schulte, H.M., Chrousos, G.P., Loriaux, D.L., Hall, N.R. and Goldstein, A.L., The thymus-adrenal connection: thymosin has corticotropin-releasing activity in primates, Science, 222 (1983) 1353–1355.PubMedCrossRefGoogle Scholar
  21. Iurato, M.P., Chiarenza, A., Barbera, N., Cantarella, G., Lempereur, L., Drago, F., Scapagini, U. and Bernardin, R., Thymic factors influence on behavior in rodents, Pharmacol. Biochem. Beh., 44 (1993) 665–671.CrossRefGoogle Scholar
  22. Janossy, G., Thomas, J.A, Bottum, F.L., Granzer, G., Pizzolo, G., Bradstock, K.F., Wong, L., Ganeshagun, K. and Hoffbrand, AB., The human thymic microenvironment: an immunohistologic study, J. Immunol., 125 (1980) 202–212.PubMedGoogle Scholar
  23. Jenkinson, E.J., Van Ewijk, W. and Owen, J.J., Major histocompatibility complex antigen expression on the epithelium of developing thymus in normal and nude mice, J. Exp. Med., 153 (1981) 280–292.PubMedCrossRefGoogle Scholar
  24. Jennings, K.R. and Shien, H.M., The effects of synthetic thymopoietin on binding of alphabungarotoxin to rat neural membranes, Comp. Biochem. Physiol., 104 (1993) 411–413.CrossRefGoogle Scholar
  25. Le, P.T., Lazorich, S., Whichard, L.P., Yang, Y.C., Clarck, S.C., Haynes, B.F. and Singer, K.H., Human thymic epithelial cells produce IL-6, granulocyte-monocye CSF and leukemia inhibitory factor, J. Immunol., 145 (1990) 3310–3315.PubMedGoogle Scholar
  26. Le, P.T., Tuck, D.T., Dinarello, C.A., Haynes, B.F. and Singer, K.H., Thymic epithelial cells produce interleukin 1, J. Immunol., 138 (1988) 2520–2525.Google Scholar
  27. D. Gerber, H., Gerschpacher, H., Stocker, H. and Bolla, K., Treatment of active rheumatoid arthritis with slow intravenous injections of thymopentin. A double-blind placebo-controlled randomised study, Lancet, 1 (1985) 832–836.PubMedGoogle Scholar
  28. Malaise, M.G., Hazee-Hagelstein, M.T., Reuter, A.M., Vrinds-Gevaert, Y., Goldstein, G. and Franchimont, P., Thymopoietin and thymopentin enhance the levels of ACTH, beta-endorphin and beta-lipotropin from rat pituitary cells in vitro, Acta Endocrinol., 115 (1987) 455–460.PubMedCrossRefGoogle Scholar
  29. Malaise, M.G., Hauwaert, C., Franchimont, P., Danneskiold-Samsoe, B., Bach-Andersen, R., Gross, Michael, S.D., Taguchi, O. and Nishizuka, Y., Effect of neonatal thymectomy on ovarian development and plasma LH, FSH, GH and PRL in the mouse, Biol. Reprod., 22 (1976) 343–350.Google Scholar
  30. Michael, S.D., Taguchi, O. and Nishizuka, Y., Effect of neonatal thymectomy on ovarian development and plasma LH, FSH, GH, and PRL in the mouse, Biol. Reprod., 22 (1980) 343–350.PubMedGoogle Scholar
  31. Milenkovic, L., Lyson, K., Aguila, M.C. and McCann, S.M., Effect of thymosin alpha 1 on hypothalamic hormone release, Neuroendocrinology, 56 (1992) 674–679.PubMedCrossRefGoogle Scholar
  32. Milenkovic, L. and McCann, S.M., Effects of thymosin alpha-1 on pituitary hormone release, Neuroendocrinology, 55 (1992) 14–19.PubMedCrossRefGoogle Scholar
  33. Mocchegiani, E., Amadio, L. and Fabris, N., Neuroendocrine-thymus interactions. I. In vitro modulation of thymic factor secretion by thyroid hormones, J. Endocrinol.Invest., 13 (1990) 139–147.PubMedGoogle Scholar
  34. Mocchegiani, E., Paolucci, P., Balsamo, A., Cacciari, E. and Fabris, N., Influence of growth hormone on thymic endocrine activity in humans, Horm. Res., 33 (1990) 248–255.PubMedCrossRefGoogle Scholar
  35. Nishizuka, Y. and Sakakura, T., Thymus and reproduction: sex-linked dysgenesis of the gonad after neonatal thymectomy in mice, Science, (1969) 753–755.Google Scholar
  36. Nonoyama, S., Nakayama, M., Shiohara, T. and Yata, J., Only dull CD3+ thymocytes bind to thymic epithelial cells. The binding is elicited by both CD2/LFA-3 and LFA-1/ICAM-1 interactions, Eur. J. Immunol., 19 (1989) 1631–1635.PubMedCrossRefGoogle Scholar
  37. Palaszynski, E.W., Moody, T.W., O’Donohue, T.L. and Goldstein, A.L., Thymosin al-like peptides: localization and biochemical characterization in the rat brain and pituitary gland, Peptides, 4 (1983) 463–467.PubMedCrossRefGoogle Scholar
  38. Pelletier, M., Montplaisir, S., Dardenne, M. and Bach, J.F., Thymic hormone activity and spontaneous auotimmunity in dwarf and their littermates, Immunology, 30 (1976) 783–788.PubMedGoogle Scholar
  39. Pierpaoli, W., Kopp, H.G. and Bianchi, E., Interdependence of thymic and neuroendocrine functions in ogtogeny, Clin. Exp. Immunol., 24 (1976) 501–506.PubMedGoogle Scholar
  40. Prepin, J., Fetal thymus and thymulin stimulate the in vitro proliferation of oogonia in the fetal rat ovary, C R Acad. Sci. [III], 313 (1991) 407–411.Google Scholar
  41. Prepin, J., Fetal thymus and thymulin stimulate in vitro proliferation of gonocytes in the fetal testis in rats, C R Acad. Sci. [III], 316 (1993) 451–454.Google Scholar
  42. Rebar, R.W., Morandini, I.C., Bernirschke, K. and Petze, J. E., Reduced gonadotropins in athymic mice:prevention by thymic transplantation, Endocrinology, 107 (1980) 2130–2132.PubMedCrossRefGoogle Scholar
  43. Rebar, R.W., Miyake, A., Low, T.L. and Goldstein, A.L., Thymosin stimulates secretion of luteinizing hormone-releasing factor, Science, 214 (1981) 669–671.PubMedCrossRefGoogle Scholar
  44. Rebar, R.W., Morandini, I.C., Petze, J.E. and Erickson, G.F., Hormonal basis of reproductive defects in athymic mice: gonadotropins and testosterone in males, Biol. Reprod., 27 (1982) 1267–1276.PubMedCrossRefGoogle Scholar
  45. Reichhart, R., Zeppezauer, M. and Jornvall, H., Preparations of hemeostatic thymus hormone consist predominantly of histones 2A and 2B and suggest additonal histone functions, Proc. Natl. Acad. Sci., 82 (1985) 4871–4875.PubMedCrossRefGoogle Scholar
  46. Ruitenberg, E.J. and Berkvens, J.M., The morphology of the endocrine system in congenitally athymic (nude) mice, J. Pathol., 121 (1977) 225–231.PubMedCrossRefGoogle Scholar
  47. Safieh, B., Venn, G.E., Ritter, M., Singh, S., Buckingham, J.C. and Kendall, M.D., Plasma thymulin concentations in cardiac patients: involvement with the hypothalamo-pituitary-adrenal axis, J. Physiol. (Paris), 438 (1991) 50p.Google Scholar
  48. Safieh-Garabedian, B., Ahmed, K., Khamashta, M.A. and Hughes, G.R.V., Thymulin modulates cytokine release by peripheral blood mononuclear cells: a comparison between healthy volunteers and patients with systemic lupus erythematosus, Int. Arch Allergy Immunol., 101 (1993) 126–131.PubMedCrossRefGoogle Scholar
  49. Safieh-Garabedian, B., Jalakhian, R.H., Saadé, N.E., Haddad, J.J., Jabbur, S.J. and Kanaan, S.A., Thymulin reduces hyperalgesia induced by peripheral endotoxin injectin in rats and mice, Brain Res., 717 (1996) 179–183.PubMedCrossRefGoogle Scholar
  50. Safieh-Garabedian, B., Kanaan, S.A., Jalakhian, R.H., Poole, S., Jabbur, S.J. and Saadé, N.E., Hyperalgesia induced by low doses of thymulin injections: possible involvement of prostaglandin E2, J. Neuroimmunol., 73 (1997) 162–168.PubMedCrossRefGoogle Scholar
  51. Savino, W., Gagnerault, M.C., Bach, J.F. and Dardenne, M., Neuroendocrine control of thymic hormonal production. II. Stimulatory effects of endogenous opioids on thymulin production by cultured human and murine thymic epithelial cells, Life Sci., 46 (1990) 1687–1697.PubMedCrossRefGoogle Scholar
  52. Savino, W., Wolff, B., Aratan-Spire, S. and Dardenne, M., Thymic hormone containing cells. IV. Fluctuations in the thyroid hormone levels in vivo can modulate the secretion of thymulin by the epithelial cells of young mouse thymus, Clin. Exp. Immunol., 55 (1984) 629–635.PubMedGoogle Scholar
  53. Spangelo, B.L., Hall, N.R., Dunn, A.J. and Goldstein, A.L., Thymosin fraction 5 stimulates the release of prolactin from cultured GH3 cells, Life Sci., 40 (1987) 283–288.PubMedCrossRefGoogle Scholar
  54. Spangelo, B.L., Judd, A.M., Ross, P.C., Login, I.S., Jarvis, W.D., Badamchian, M., Goldstein, A.L. and Mac Leod, R.M., Thymosin fraction 5 stimulates prolactin and growth hormone release from anterior pituitary, Endocrinology, 121 (1987) 2035–2043.PubMedCrossRefGoogle Scholar
  55. Su, Y., Ho, K.L., Dalakas, M.C. and Mutchnick, M.G., Localization of immunoreactive thymosin alpha 1 in astrocytes of normal human brain, Ann. Neurol., 26 (1989) 277–280.PubMedCrossRefGoogle Scholar
  56. Timsit, J., Savino, W., Safieh, B., Chanson, P., Gagnerault, M.C., Bach, J.F. and Dardenne, M., Effects of growth hormone and insulin-like growth factor 1 in thymic hormonal function in man, J. Clin. Endocrin. Metab., 75 (1992) 1251–1260.CrossRefGoogle Scholar
  57. Van Ewijk, W., T-cell differentiation is influenced by thymic microenvironmeuts, Ann. Rev. Immunol., 9 (1991) 591–615.CrossRefGoogle Scholar
  58. Van Ewijk, W., Ron, Y., Monaco, J., Kapplier, J., Marrack, P., Le Meur, H., Gerlinger, P., Durand, B., Benoist, C. and Mattis, D., Compartimentalization of MHC class II gene expression in transgenic mice, Cell, 53 (1988) 357–370.PubMedCrossRefGoogle Scholar
  59. Zaidi, S.A.A., Kendall, M.D., Gillham, B. and Jones, M.T., The release of LH from pituitaries perifused with thymic extracts, Thymus, 12 (1988) 253–264.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Mireille Dardenne
    • 1
  • Bared Safieh-Garabedian
    • 2
  • Jean-Marie Pleau
    • 1
  1. 1.CNRS UMR 8603 – Université Paris VHôpital NeckerParisFrance
  2. 2.Department of Biology, Faculty of Arts and ScienceAmerican University of BeirutBeirutLebanon

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