Melatonin and the Immune System Therapeutic Potential in Cancer, Viral Diseases, and Immunodeficiency States

  • Georges J. M. Maestroni


Neuroimmunomodulation refers to the continuous interaction between the nervous and immune systems. It is now well recognized that a main actor of this connection is the pineal hormone melatonin. T helper (Th) cells bear G-protein-coupled melatonin cell membrane receptors and, perhaps, melatonin nuclear receptors. Activation of melatonin receptors enhances the release of T helper cell type 1 (Th1) cytokines, such as interferon-γ(IFN-γ) and interleukin-2 (IL-2), as well as of novel opioid cytokines which crossreact immunologically with both interleukin-4 (IL-4) and dynorphin. Melatonin has been reported to also enhance the production of interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-12 (IL-12) in human monocytes. These mediators may counteract stress-induced immunodepression and other secondary immunodeficiencies, protect mice against lethal viral and bacterial diseases, synergize with interleukin-2 (IL-2) in cancer patients, and influence hematopoiesis. In cancer patients, melatonin seems to be required for the effectiveness of low-dose IL-2 in neoplasias that are generally resistant to IL-2 alone. Hematopoiesis is apparently influenced by the action of the melatonin-induced-opioids (MIO) on κ-opioid receptors present on stromal bone marrow macrophages. Most interestingly, IFN-γ and colony-stimulating factors (CSFs) may modulate the production of melatonin in the pineal gland. A hypothetical pineal-immune-hematopoietic network is therefore taking shape. From the immunopharmacological and ethical point of view, clinical studies on the effect of melatonin in combination with IL-2 or other cytokines in viral disease including human immunodeficiency virus-infected patients and cancer patients are needed. In conclusion, melatonin seems to play a crucial role in the homeostatic interactions between the brain and the immune-hematopoietic system and deserves to be further studied to identify its therapeutic indications and its adverse effects.


Pineal Gland Melatonin Receptor Melatonin Administration Exogenous Melatonin Endogenous Melatonin 
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  1. Ader R, Cohen N, Feiten D (1995) Psychoneuroimmunology: interactions between the nervous system and the immune system. Lancet 345 (8942): 99–103.PubMedCrossRefGoogle Scholar
  2. Ader R, Feiten DL, Cohen N (eds) (1991) Psychoneuroimmunology 2. (ed) Academic Press, San Diego.Google Scholar
  3. Angeli A, Gatti G, Sartori ML, Del Ponte D, Cerignola R (1988) Effect of exogenous melatonin on human natural killer (NK) cell activity. An approach to the immunomodulatory role of the pineal gland. In: Gupta D, Attanasio A, Reiter RJ (eds) The Pineal Gland and Cancer. Müller and Bass, Tübingen, pp 145–157.Google Scholar
  4. Banks RE, Patel PM, Selby PJ (1995) Interleukin-12: a new player in cytokine therapy. Br J Cancer 71:655–659.PubMedCrossRefGoogle Scholar
  5. Barath P, Csaba G (1974) Histological changes in the lung, thymus and adrenal one and half year after pinealectomy. Acta Biol Acad Sci Hung 25:123–125.PubMedCrossRefGoogle Scholar
  6. Becker J, Veit G, Handgretinger R, Attanasio G, Bruchelt G, Treuner I, Niethammer D, Gupta D (1988) Circadian variations in the immunomodulatory role of the pineal gland. Neuroendocrinol Lett 10:65–80.Google Scholar
  7. Ben-Nathan D, Maestroni GJM, Conti A (1995) Protective effect of melatonin in mice infected with encephalitis viruses. Arch Virol 140:223–230.PubMedCrossRefGoogle Scholar
  8. Ben-Nathan D, Maestroni GJM, Conti A (1996) Protective effect of melatonin in viral and bacterial infections. Abstract, 2nd Locarno Meeting on Neuroendocrinoimmunology Therapeutic potential of the Pineal Hormone Melatonin, May 5–8, Locarno, Switzerland.Google Scholar
  9. Bernstein ZP, Porter MM, Gould M, Lipman B, Bluman EM, Stewart CC, Hewitt RG, Fyfe G, Poiesz B, Caligiuri MA (1995) Prolonged administration of low-dose interleukin-2 in human immunodeficiency virus-associated malignancy results in selective expansion on innate immune effectors without significant clinical toxicity. Blood 86:3287–3294.PubMedGoogle Scholar
  10. Bindoni M, Cambria A (1968) Effects of pinealectomy on the in vivo and the in vitro biosynthesis of nucleic acids and on the mitotic rate in some organs of the rat. Arch Sci Biol (Bologna) 52: 271–283.Google Scholar
  11. Blask DE (1993) Melatonin in oncology. In: Yu H-S, Reiter RJ (eds) Melatonin. Biosynthesis, Physiological Effects, and Clinical Applications. CRC Press, Boca Raton, pp 447–477.Google Scholar
  12. Bonilla E, Valerofuenmajor N, Pons H, Chacin-Bonilla L (1997) Melatonin protects mice infected with Venezuelan equine encephalomyelitis virus. Cell Mol Life Sci 53:430–434.PubMedCrossRefGoogle Scholar
  13. Carlberg C, Wiesenberg I (1995) The orphan receptor family RZR/ROR, melatonin and 5-lipoxygenase: an unexpected relationship. J Pineal Res 18:171–178.PubMedCrossRefGoogle Scholar
  14. Caroleo MC, Frasca D, Nistico G, Doria G (1992) Melatonin as immunomodulator in immunodeficient mice. Immunopharmacology 23:81–89.PubMedCrossRefGoogle Scholar
  15. Champney TH, McMurray DN (1991) Spleen morphology and lymphoproliferative activity in short photoperiod exposed hamsters. In: Fraschini F, Reiter RJ (eds) Role of melatonin and pineal peptides in neuroimmunomodulation. Plenum Publ Co, London, pp 219–225.CrossRefGoogle Scholar
  16. Colombo LL, Chen G-J, Lopez MC, Watson RR (1992) Melatonin induced increase in gamma-interferon production by murine splenocytes. Immunol Lett 33:123–126.PubMedCrossRefGoogle Scholar
  17. Conti A, Maestroni GJM (1995) The clinical neuroimmunotherapeutic role of melatonin in oncology. J Pineal Res 19:103–110.PubMedCrossRefGoogle Scholar
  18. Conti A, Haran-Ghera N, Maestroni GJM (1992) Role of pineal melatonin and melatonin-inducedimmuno-opioids in murine leukemogenesis. Med Oncol Tumor Pharmacother 9:87–92.PubMedGoogle Scholar
  19. Csaba G, Barath P (1975) Morphological changes of thymus and the thyroid gland after postnatalextirpation of pineal body. Endocrinol exp 9:59–67.PubMedGoogle Scholar
  20. Csaba G, Bodocky M, Fischer J, Acs T (1965) The effect of pinealectomy and thymectomy on the immune capacity of the rat. Experientia 22:168–175.CrossRefGoogle Scholar
  21. Del Gobbo V, Libri V, Villani N, Caliò R, Nstico G (1989) Pinealectomy inhibits interleukin-2 production and natural killer activity in mice. Int J Immunopharmacol 11:567–577.PubMedCrossRefGoogle Scholar
  22. Del Prete G, Maggi E, Romagnani S (1994) Human Th1 and Th2 cells: Functional properties, mechanisms of regulation and role in disease. Lab Invest 70:299–307.PubMedGoogle Scholar
  23. Garcia-Mauriño S, Gonzales-Haba MG, Calvo JR, Rafìi-El-Idrissi M, Sanchez-Margalet V, Goberna R, Guerrero JM (1997) Melatonin enhances I1–2, I1–6, and IFN-γ production by human circulating CD4+ cells. J Immunology 159: 574–581.Google Scholar
  24. Garcia-Perganeda A, Pozo D, Guerrero JM, Calvo JR (1997) Signal transduction for melatonin in human lymphocytes. Involvement of a pertussis toxin-sensitive G protein. J Immunol 159:3774–3781.Google Scholar
  25. Giordano M, Palermo MS (1991) Melatonin-induced enhancement of antibody dependent cellular cytotoxicity. J Pineal Res 10:117–121.PubMedCrossRefGoogle Scholar
  26. Guerrero J-M, Garcia-Maurino S, Gil-Haba M, Rafii-El-Idrissi M, Pozo D, Garcia-Perganeda A, Calvo JR (1996) Mechanisms of action on the human immune system: Membrane receptors versus nuclear receptors. In: Maestroni GJM, Conti A, Reiter RJ (eds) Therapeutic potential of the Pineal Hormone Melatonin. Karger, Basel, pp 43–52.Google Scholar
  27. Haldar C, Haussler D, Gupta D (1992) Response of CFU-GM(colony forming units for granulocytes and macrophages) from intact and pinealectomized rat bone marrow to macrophage colony stimulating factor (rGM-CSF) and human recombinant erythropoietin (rEPO). Prog Brain Res 91:323–325.PubMedCrossRefGoogle Scholar
  28. Hansson I, Holmdahl R, Mattsson R (1992) The pineal hormone melatonin exaggerates development of collagen-induced arthritis in mice. J Neuroimmunol 39: 23–31.PubMedCrossRefGoogle Scholar
  29. Hiddinga H J, Isaak DD, Lewis RV (1994) Enkephalin-containing peptides processed from proenkephalin significantly enhance the antibody-forming cell responses to antigens. J Immunol 152: 3748–3758.PubMedGoogle Scholar
  30. Hofbauer LC, Heufelder AE (1996) Endocrinology meets immunology: T lymphocytes as novel targets for melatonin. Eur J Endocrinol 134:424–425.PubMedCrossRefGoogle Scholar
  31. Jankovic BD, Isakovic S, Petrovic S (1970) Effect of pinealectomy on immune reactions in the rat. Immunology 8:1–6.Google Scholar
  32. Kinter AL, Bende SM, Hardy EC, Jackson R, Fauci AS (1995) Interleukin 2 induces CD8+ T cellmediated suppression of human immunodeficiency virus replication in CD4+ T cells and this effect overrides its ability to stimulate virus expression. Proc Natl Acad Sci USA 92:19985–10989.CrossRefGoogle Scholar
  33. Konakchieva R, Kyurkchiev S, Kehayov I, Taushanova P, Kanchev L (1995) Selective effect of methoxyndoles on the lymphocyte proliferation and melatonin binding to activated human lymphoid cells. J Neuroimmunol 63:125–132.PubMedCrossRefGoogle Scholar
  34. Lewinsky A, Zelazowsky P, Sewerynek E, Zerek-Melen G, Szudlinsky M (1989) Melatonin-induced immunosuppression of humal lymphocyte natural killer activity in vitro. J Pineal Res 7:153–164.CrossRefGoogle Scholar
  35. Lissoni P, Barni S, Ardizzoia A, Brivio F, Tancini G, Conti A, Maestroni GJM (1992) Immunological effects of a single evening subcutaneous injection of low-dose interleukin-2 in association with the pineal hormone melatonin in advanced cancer patients. J Biol Reg Homeos Agents 6:132–136.Google Scholar
  36. Lissoni P, Brivio F, Brivio O, Fumagalli L, Gramazio F, Rossi M, Emanuelli G, Alderi G, Lavorato F (1995) Immune effects of preoperative immunotherapy with high-dose subcutaneous interleukin-2 versus neuroimmunotherapy with low-dose interleukin-2 plus the neurohormone melatonin in gastrointestinal tract tumor patients. J Biol Regul Homeost Agents 9:31–33.PubMedGoogle Scholar
  37. Lissoni P, Pittalis S, Barni S, Rovelli F, Fumagalli L, Maestroni GJM (1997a) Regulation of interleukin-2/interleukin-12 interactions by the pineal gland. Int J Thymology 5:443–447.Google Scholar
  38. Lissoni P, Rovelli F, Brivio F, Pittalis S, Maestroni GJM, Fumagalli L (1997b) In vivo study of the modulatory effect of the pineal hormone melatonin on interleukin-12 secretion in response to interleukin-2. Int J Thymology 5:482–486.Google Scholar
  39. Maestroni GJM (1993) The immunoneuroendocrine role of melatonin. J Pineal Res 14:1–10.PubMedCrossRefGoogle Scholar
  40. Maestroni GJM (1995) T helper 2 lymphocytes as a peripheral target of melatonin. J Pineal Res 18:84–89.PubMedCrossRefGoogle Scholar
  41. Maestroni GJM, Conti A (1989) Beta-endorphin and dynorphin mimic the circadian immuno-enhancing and anti-stress effects of melatonin. Int J Immunopharmacol 11:333–340.PubMedCrossRefGoogle Scholar
  42. Maestroni GJM, Conti A (1990) The pineal neurohormone melatonin stimulates activated CD4+, Thy-1+ cells to release opioid agonist(s) with immunoenhancing and anti-stress properties. J Neuroimmunol 28:167–176.PubMedCrossRefGoogle Scholar
  43. Maestroni GJM, Conti A (1991) Anti-stress role of the melatonin-immuno-opioid network. Evidence for a physiological mechanism involving T cell-derived, immunoreactive? β-endorphin and MET-enkephalin binding to thymic opioid receptors. Int J Neurosci 61:289–298.PubMedCrossRefGoogle Scholar
  44. Maestroni GJM, Conti A (1993) Melatonin in relation to the immune system. In: Yu H-S, Reiter RJ (eds) Melatonin. Biosynthesis, Physiological effects and Clinical Applications. CRC Press, Boca Raton, pp 290–306.Google Scholar
  45. Maestroni GJM, Conti A (1996) Melatonin and the immune-hematopoietic system. Therapeutic and adverse pharmacological correlates. Neuroimmunomodulation 3:325–332.Google Scholar
  46. Maestroni GJM, Pierpaoli W (1981) Pharmacological control of the hormonally modulated immune response. In: Ader R (eds) Psychoneuroimmunology. Academic Press, New York, pp 405–425.Google Scholar
  47. Maestroni GJM, Conti A, Pierpaoli W (1986) Role of the pineal gland in immunity. Circadian synthesis and release of melatonin modulates the antibody response and antagonize the imuno- suppressive effect of corticosterone. J Neuroimmunol 13:19–30.Google Scholar
  48. Maestroni GJM, Conti A, Pierpaoli W (1987) Role of the pineal gland in immunity: II. Melatonin enhances the antibody response via an opiatergic mechanism. Clin Exp Immunol 68:384–391.Google Scholar
  49. Maestroni GJM, Conti A, Pierpaoli W (1988) Role of the pineal gland in immunity. III. Melatonin antagonizes the immunosuppressive effect of acute stress via an opiatergic mechanism. Immunology 63:465–469.Google Scholar
  50. Maestroni GJM, Conti A, Reiter RJ (eds) (1994a) Advances in Pineal Research 7. Reiter RJ (ed). John Libbey & Co., London.Google Scholar
  51. Maestroni GJM, Covacci V, Conti A (1994b) Hematopoietic rescue via T-cell-dependent, endogenous GM-CSF by the pineal neurohormone melatonin in tumor bearing mice. Cancer Res 54:2429–2432.PubMedGoogle Scholar
  52. Maestroni GJM, Conti A, Lissoni P (1994c) Colony-stimulating activity and hematopoietic rescue from cancer chemothereapy compounds are induced by melatonin via endogenous interleukin 4. Cancer Res 54:4740–4743.PubMedGoogle Scholar
  53. Maestroni G, Hertens E, Galli P, Conti A, Pedrinis E (1996) Melatonin-induced T-helper cell hematopoietic cytokines resembling both interleukin-4 and dynorphin. J Pineal Res 21:131–139.PubMedCrossRefGoogle Scholar
  54. Morrey MK, McLachlan JA, Serkin CD, Bakouche O (1994) Activation of human monocytes by the pineal neurohormone melatonin. J Immunol 153:2671–2680.PubMedGoogle Scholar
  55. Neri B, Fiorelli C, Moroni F, Nicita G, Paoletti MC, Ponchietti R, Raugei A, Santoni G, Trippitelli A, Grechi G (1994) Modulation of human lymphobalstoid interferon activity by melatonin in metastatic renal cell carcinoma. A phase II study. Cancer 73:3015–3019.Google Scholar
  56. Palermo MS, Vermeulen M, Giordano M (1994) Modulation of antibody-dependent cellular cytotoxicity by pineal gland. In: Maestroni GJM, Conti A, Reiter RJ (eds) Advances in Pineal Research. John Libbey, London, pp 143–147.Google Scholar
  57. Pioli C, Caroleo MC, Nistico G, Doria G (1993) Melatonin increases antigen presentation and amplifies specific and non specific signals for T-cell proliferation. Int J Immunopharmacol 15:463–469.PubMedCrossRefGoogle Scholar
  58. Poon AM, Liu ZM, Pang CS, Brown GM, Pang SF (1994) Evidence for a direct action of melatonin on the immune system. Biol Signals 3:107–117.PubMedCrossRefGoogle Scholar
  59. Rella W, Lapin V (1978) Immunocompetence of pinealectomized and simultaneously pinealectomized and thymectomized rats. Oncology 33:3–6.CrossRefGoogle Scholar
  60. Reppert SM, Weaver DR (1995) Melatonin madness. Cell 83:1059–1062.PubMedCrossRefGoogle Scholar
  61. Sei S, Akiyoshi H, Bernard J, Venzon DJ, Fox CH, Schwartzentruber DJ, Anderson BD, Kopp JB, Mueller BU, Pizzo PA (1996) Dynamics of virus versus host intercation in children with human immunodeficiency virus type 1 infection. J Infect Dis 173:1485–1490.PubMedCrossRefGoogle Scholar
  62. Spector NH, Dolina S, Cornelissen G, Halberg F, Markovic BM, Jankovic BD (1996) Neuroimmuno- modulation: neuroimmune interactions with the environment. In: Blatteis CM (eds) Handbook of Physiology: The Environment. Amer Physiol Society, Bethesda, pp 1437–1549.Google Scholar
  63. Vaughan MK, Reiter RJ (1971) Transient hypertrophy of the ventral prostate and coagulating glands and accelerated thymic involution following pinealectomy in the mouse. Texas Rep Biol Med 29:579–586.Google Scholar
  64. Wichmann M, Zellweger R, DeMaso A, Ayala A, Chaudry I (1996) Melatonin administrationattenuates depressed immune functions trauma-hemorrhage. J Surg Res 63:256–262.PubMedCrossRefGoogle Scholar
  65. Withyachumnarnkul B, Nonaka KO, Santana C, Attia AM, Reiter RJ (1990) Interferon-gamma modulates melatonin production in rat pineal gland in organ culture. J Interferon Res 10: 403–411.PubMedCrossRefGoogle Scholar
  66. Young MRI, Young ME, Kim K (1988) Regulation of tumor-induced myelopoiesis and the associated immune suppressor cells in mice bearing metastatic Lewis lung carcinoma by prostaglandin E2. Cancer Res 48:6826–6831.PubMedGoogle Scholar
  67. Yu H-S, Reiter RJ (eds) (1993) Melatonin. Biosynthesis, Physiological Effects, and Clinical Applications. CRC Press, Boca Raton.Google Scholar

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  • Georges J. M. Maestroni

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