Journal Mobile Options
Table of Contents
Vol. 15, No. 2, 2008
Issue release date: August 2008
Neuroimmunomodulation 2008;15:93–101

Immunomodulation by Melatonin: Its Significance for Seasonally Occurring Diseases

Srinivasan V. · Spence D.W. · Trakht I. · Pandi-Perumal S.R. · Cardinali D.P. · Maestroni G.J.
aDepartment of Physiology, School of Medical Sciences, University Sains Malaysia, Kubang Kerian, Malaysia; bCenter for Addiction and Mental Health, and cSleep and Neuropsychiatry Institute, Toronto, Ont., Canada; dDivision of Clinical Pharmacology and Experimental Therapeutics, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, N.Y., USA; eDepartamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina; fCenter for Experimental Pathology, Cantonal Institute of Pathology, Locarno, Switzerland

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Melatonin is not only synthesized by the pineal gland but also in many other organs and tissues of the body, particularly by lymphoid organs such as the bone marrow, thymus and lymphocytes. Melatonin participates in various functions of the body, among which its immunomodulatory role has assumed considerable significance in recent years. Melatonin has been shown to be involved in the regulation of both cellular and humoral immunity. Melatonin not only stimulates the production of natural killer cells, monocytes and leukocytes, but also alters the balance of T helper (Th)-1 and Th-2 cells mainly towards Th-1 responses and increases the production of relevant cytokines such as interleukin (IL)-2, IL-6, IL-12 and interferon-γ. The regulatory function of melatonin on immune mechanisms is seasonally dependent. This fact may in part account for the cyclic pattern of symptom expression shown by certain infectious diseases, which become more pronounced at particular times of the year. Moreover, melatonin-induced seasonal changes in immune function have also been implicated in the pathogenesis of seasonal affective disorder and rheumatoid arthritis. The clinical significance of the seasonally changing immunomodulatory role of melatonin is discussed in this review.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Cardinali DP, Pevet P: Basic aspects of melatonin action. Sleep Med Rev 1998;2:175–190.
  2. Claustrat B, Brun J, Chazot G: The basic physiology and pathophysiology of melatonin. Sleep Med Rev 2005;9:11–24.
  3. Lundmark PO, Pandi-Perumal SR, Srinivasan V, et al: Role of melatonin in the eye and ocular dysfunctions. Vis Neurosci 2006;23:853–862.
  4. Bubenik GA: Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci 2002;47:2336–2348.
  5. Konturek SJ, Konturek PC, Brzozowska I, et al: Localization and biological activities of melatonin in intact and diseased gastrointestinal tract (GIT). J Physiol Pharmacol 2007;58:381–405.
  6. Slominski A, Fischer TW, Zmijewski MA, et al: On the role of melatonin in skin physiology and pathology. Endocrine 2005;27:137–148.
  7. Carrillo-Vico A, Calvo JR, Abreu P, et al: Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and/or paracrine substance. FASEB J 2004;18:537–539.
  8. Naranjo MC, Guerrero JM, Rubio A, et al: Melatonin biosynthesis in the thymus of humans and rats. Cell Mol Life Sci 2007;64:781–790
  9. Skwarlo-Sonta K: Melatonin in immunity: comparative aspects. Neuro Endocrinol Lett 2002;23(suppl 1):61–66.

    External Resources

  10. Maestroni GJ: The immunotherapeutic potential of melatonin. Expert Opin Investig Drugs 2001;10:467–476.
  11. Nelson RJ, Demas GE: Role of melatonin in mediating seasonal energetic and immunologic adaptations. Brain Res Bull 1997;44:423–430.
  12. Nelson RJ, Demas GE: Seasonal changes in immune function. Q Rev Biol 1996;71:511–548.
  13. Nelson RJ, Drazen DL: Melatonin mediates seasonal changes in immune function. Ann NY Acad Sci 2000;917:404–415.
  14. Lam RW, Song C, Yatham LN: Does neuroimmune dysfunction mediate seasonal mood changes in winter depression? Med Hypotheses 2004;63:567–573.
  15. Karasek M: Melatonin, human aging, and age-related diseases. Exp Gerontol 2004;39:1723–1729.
  16. Arlt W, Hewison M: Hormones and immune function: implications of aging. Aging Cell 2004;3:209–216.
  17. Srinivasan V, Maestroni GJM, Cardinali DP, et al: Melatonin, immune function and aging. Immun Ageing 2005;2:17.
  18. Axelrod J: The pineal gland: a neurochemical transducer. Science 1974;184:1341–1348.
  19. Moore RY: Neural control of the pineal gland. Behav Brain Res 1996;73:125–130.
  20. Brainard GC, Hanifin JP, Rollag MD, et al: Human melatonin regulation is not mediated by the three cone photopic visual system. J Clin Endocrinol Metab 2001;86:433–436.
  21. Berson DM: Phototransduction in ganglion-cell photoreceptors. Pflugers Arch 2007;454:849–855.
  22. Maronde E, Stehle JH: The mammalian pineal gland: known facts, unknown facets. Trends Endocrinol Metab 2007;18:142–149.
  23. Bergiannaki JD, Soldatos CR, Paparrigopoulos TJ, et al: Low and high melatonin excretors among healthy individuals. J Pineal Res 1995;18:159–164.
  24. Leger D, Laudon M, Zisapel N: Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy. Am J Med 2004;116:91–95.
  25. Wehr TA: Effect of seasonal changes in daylength on human neuroendocrine function. Horm Res 1998;49:118–124.
  26. Ribelayga C, Pevet P, Simonneaux V: HIOMT drives the photoperiodic changes in the amplitude of the melatonin peak of the Siberian hamster. Am J Physiol Regul Integr Comp Physiol 2000;278:R1339–R1345.
  27. Garidou ML, Vivien-Roels B, Pevet P, et al: Mechanisms regulating the marked seasonal variation in melatonin synthesis in the European hamster pineal gland. Am J Physiol Regul Integr Comp Physiol 2003;284:R1043–R1052.
  28. Garidou ML, Diaz E, Calgari C, et al: Transcription factors may frame Aa-nat gene expression and melatonin synthesis at night in the Syrian hamster pineal gland. Endocrinology 2003;144:2461–2472.
  29. Honma K, Honma S, Kohsaka M, et al: Seasonal variation in the human circadian rhythm: dissociation between sleep and temperature rhythm. Am J Physiol 1992;262:R885–R891
  30. Ueno-Towatari T, Norimatsu K, Blazejczyk K, et al: Seasonal variations of melatonin secretion in young females under natural and artificial light conditions in Fukuoka, Japan. J Physiol Anthropol 2007;26:209–215.

    External Resources

  31. Carrillo-Vico A, Reiter RJ, Lardone PJ, et al: The modulatory role of melatonin on immune responsiveness. Curr Opin Investig Drugs 2006;7:423–431.
  32. Dubocovich ML, Markowska M: Functional MT1 and MT2 melatonin receptors in mammals. Endocrine 2005;27:101–110.
  33. Drazen DL, Nelson RJ: Melatonin receptor subtype MT2 (Mel 1b) and not mt1 (Mel 1a) is associated with melatonin-induced enhancement of cell-mediated and humoral immunity. Neuroendocrinology 2001;74:178–184.
  34. Benitez-King G: Melatonin as a cytoskeletal modulator: implications for cell physiology and disease. J Pineal Res 2006;40:1–9.
  35. Cardinali DP, Freire F: Melatonin effects on brain. Interaction with microtubule protein, inhibition of fast axoplasmic flow and induction of crystalloid and tubular formations in the hypothalamus. Mol Cell Endocrinol 1975;2:317–330.
  36. Garcia-Maurino S, Pozo D, Calvo JR, et al: Correlation between nuclear melatonin receptor expression and enhanced cytokine production in human lymphocytic and monocytic cell lines. J Pineal Res 2000;29:129–137.
  37. Maestroni GJ, Conti A, Pierpaoli W: Role of the pineal gland in immunity. Circadian synthesis and release of melatonin modulates the antibody response and antagonizes the immunosuppressive effect of corticosterone. J Neuroimmunol 1986;13:19–30.
  38. Guerrero JM, Reiter RJ: Melatonin-immune system relationships. Curr Top Med Chem 2002;2:167–179.
  39. Cardinali DP, Esquifino AI, Maestroni GJM, et al: Circadian organization of the immune response: lessons from the adjuvant arthritis model; in Pandi-Perumal SR, Cardinali DP, Chrousos G (eds): Neuroimmunology of Sleep. New York, Springer, 2007, pp 59–84.
  40. Pandi-Perumal SR, Zisapel N, Srinivasan V, et al: Melatonin and sleep in aging population. Exp Gerontol 2005;40:911–925.
  41. Miller SC, Pandi-Perumal SR, Esquifino AI, et al: The role of melatonin in immunoenhancement: potential application in cancer. Int J Exp Pathol 2006;87:81–87.
  42. Garcia-Maurino S, Gonzalez-Haba MG, Calvo JR, et al: Melatonin enhances IL-2, IL-6, and IFN-gamma production by human circulating CD4+ cells: a possible nuclear receptor-mediated mechanism involving T helper type 1 lymphocytes and monocytes. J Immunol 1997;159:574–581.
  43. Liu F, Ng TB, Fung MC: Pineal indoles stimulate the gene expression of immunomodulating cytokines. J Neural Transm 2001;108:397–405.
  44. Lissoni P, Rovelli F, Brivio F, et al: Circadian secretions of IL-2, IL-12, IL-6 and IL-10 in relation to the light/dark rhythm of the pineal hormone melatonin in healthy humans. Nat Immun 1998;16:1–5.
  45. Mitchell WA, Meng I, Nicholson SA, et al: Thymic output, ageing and zinc. Biogerontology 2006;7:461–470.
  46. Gruver AL, Hudson LL, Sempowski GD: Immunosenescence of ageing. J Pathol 2007;211:144–156.
  47. Quaglino D, Capri M, Bergamini G, et al: Age-dependent remodeling of rat thymus. Morphological and cytofluorimetric analysis from birth up to one year of age. Eur J Cell Biol 1998;76:156–166.
  48. Csaba G, Barath P: Morphological changes of thymus and the thyroid gland after postnatal extirpation of pineal body. Endocrinol Exp 1975;9:59–67.
  49. Oner H, Kus I, Oner J, et al: Possible effects of melatonin on thymus gland after pinealectomy in rats. Neuro Endocrinol Lett 2004;25:115–118.
  50. Tian YM, Li PP, Jiang XF, et al: Rejuvenation of degenerative thymus by oral melatonin administration and the antagonistic action of melatonin against hydroxyl radical-induced apoptosis of cultured thymocytes in mice. J Pineal Res 2001;31:214–221.
  51. Sainz RM, Mayo JC, Uria H, et al: The pineal neurohormone melatonin prevents in vivo and in vitro apoptosis in thymocytes. J Pineal Res 1995;19:178–188.
  52. Sainz RM, Mayo JC, Reiter RJ, et al: Melatonin regulates glucocorticoid receptor: an answer to its antiapoptotic action in thymus. FASEB J 1999;13:1547–1556.
  53. Presman DM, Hoijman E, Ceballos NR, et al: Melatonin inhibits glucocorticoid receptor nuclear translocation in mouse thymocytes. Endocrinology 2006;147:5452–5459.
  54. Mocchegiani E, Bulian D, Santarelli L, et al: The immuno-reconstituting effect of melatonin or pineal grafting and its relation to zinc pool in aging mice. J Neuroimmunol 1994;53:189–201.
  55. Pozo D, Delgado M, Fernandez-Santos JM, et al: Expression of the Mel1a-melatonin receptor mRNA in T and B subsets of lymphocytes from rat thymus and spleen. FASEB J 1997;11:466–473.
  56. Carrillo-Vico A, Garcia-Perganeda A, Naji L, et al: Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system. Cell Mol Life Sci 2003;60:2272–2278.
  57. Champney TH, Prado J, Youngblood T, et al: Immune responsiveness of splenocytes after chronic daily melatonin administration in male Syrian hamsters. Immunol Lett 1997;58:95–100.
  58. Akbulut KG, Gonul B, Akbulut H: The effects of melatonin on humoral immune responses of young and aged rats. Immunol Invest 2001;30:17–20.
  59. Moore CB, Siopes TD: Effect of melatonin supplementation on the ontogeny of immunity in the Large White turkey poult. Poult Sci 2002;81:1898–1903.
  60. Maestroni GJ, Conti A, Pierpaoli W: The pineal gland and the circadian, opiatergic, immunoregulatory role of melatonin. Ann NY Acad Sci 1987;496:67–77.
  61. Maestroni GJ, Conti A: Beta-endorphin and dynorphin mimic the circadian immunoenhancing and anti-stress effects of melatonin. Int J Immunopharmacol 1989;11:333–340.
  62. Maestroni GJ, Conti A: The pineal neurohormone melatonin stimulates activated CD4+, Thy-1+ cells to release opioid agonist(s) with immunoenhancing and anti-stress properties. J Neuroimmunol 1990;28:167–176.
  63. Castrillon PO, Esquifino AI, Varas A, et al: Effect of melatonin treatment on 24-h variations in responses to mitogens and lymphocyte subset populations in rat submaxillary lymph nodes. J Neuroendocrinol 2000;12:758–765.
  64. Moore CB, Siopes TD: Melatonin enhances cellular and humoral immune responses in the Japanese quail (Coturnix coturnix japonica) via an opiatergic mechanism. Gen Comp Endocrinol 2003;131:258–263.
  65. Calcagni E, Elenkov I: Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases. Ann NY Acad Sci 2006;1069:62–76.
  66. Chaouat G: The Th1/Th2 paradigm: still important in pregnancy? Semin Immunopathol 2007;29:95–113.
  67. Nunnari G, Nigro L, Palermo F, et al: Reduction of serum melatonin levels in HIV-1-infected individuals’ parallel disease progression: correlation with serum interleukin-12 levels. Infection 2003;31:379–382.
  68. Moore CB, Siopes TD: Enhancement of cellular and humoral immunity following embryonic exposure to melatonin in turkeys (Meleagris gallopavo). Gen Comp Endocrinol 2005;143:178–183.
  69. Maestroni GJ, Conti A: Melatonin and the immune-hematopoietic system therapeutic and adverse pharmacological correlates. Neuroimmunomodulation 1996;3:325–332.
  70. Maestroni GJ: Is hematopoiesis under the influence of neural and neuroendocrine mechanisms? Histol Histopathol 1998;13:271–274.
  71. Currier NL, Sun LZ, Miller SC: Exogenous melatonin: quantitative enhancement in vivo of cells mediating non-specific immunity. J Neuroimmunol 2000;104:101–108.
  72. Maestroni GJ, Conti A, Lissoni P: Colony-stimulating activity and hematopoietic rescue from cancer chemotherapy compounds are induced by melatonin via endogenous interleukin 4. Cancer Res 1994;54:4740–4743.
  73. Maestroni GJ, Covacci V, Conti A: Hematopoietic rescue via T-cell-dependent, endogenous granulocyte-macrophage colony-stimulating factor induced by the pineal neurohormone melatonin in tumor-bearing mice. Cancer Res 1994;54:2429–2432.
  74. Minagar A, Shapshak P, Fujimura R, et al: The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis. J Neurol Sci 2002;202:13–23.
  75. Zhang S, Li W, Gao Q, et al: Effect of melatonin on the generation of nitric oxide in murine macrophages. Eur J Pharmacol 2004;501:25–30.
  76. Pena C, Rincon J, Pedreanez A, et al: Chemotactic effect of melatonin on leukocytes. J Pineal Res 2007;43:263–269.
  77. Nelson RJ, Demas GE, Klein Sl, et al: The influence of season, photoperiod, and pineal melatonin on immune function. J Pineal Res 1995;19:149–165.
  78. Bilbo SD, Nelson RJ: Photoperiod influences the effects of exercise and food restriction on an antigen-specific immune response in Siberian hamsters. Endocrinology 2004;145:556–564.
  79. Bilbo SD, Nelson RJ: Sex differences in photoperiodic and stress-induced enhancement of immune function in Siberian hamsters. Brain Behav Immun 2003;17:462–472.
  80. Bilbo SD, Dhabhar FS, Viswanathan K, et al: Photoperiod affects the expression of sex and species differences in leukocyte number and leukocyte trafficking in congeneric hamsters. Psychoneuroendocrinology 2003;28:1027–1043.
  81. Prendergast BJ, Bilbo SD, Nelson RJ: Photoperiod controls the induction, retention, and retrieval of antigen-specific immunological memory. Am J Physiol Regul Integr Comp Physiol 2004;286:R54–R60.
  82. Prendergast BJ, Hotchkiss AK, Nelson RJ: Photoperiodic regulation of circulating leukocytes in juvenile Siberian hamsters: mediation by melatonin and testosterone. J Biol Rhythms 2003;18:473–480.
  83. Bowden TJ, Thompson KD, Morgan AL, et al: Seasonal variation and the immune response: a fish perspective. Fish Shellfish Immunol 2007;22:695–706.
  84. Hazlerigg DG: What is the role of melatonin within the anterior pituitary? J Endocrinol 2001;170:493–501.
  85. Katila H, Cantell K, Appelberg B, et al: Is there a seasonal variation in the interferon-producing capacity of healthy subjects? J Interferon Res 1993;13:233–234.
  86. Shearer WT, Lee BN, Cron SG, et al: Suppression of human anti-inflammatory plasma cytokines IL-10 and IL-1RA with elevation of proinflammatory cytokine IFN-gamma during the isolation of the Antarctic winter. J Allergy Clin Immunol 2002;109:854–857.
  87. Dowell SF: Seasonal variation in host susceptibility and cycles of certain infectious diseases. Emerg Infect Dis 2001;7:369–374.
  88. Wearing HJ, Rohani P: Ecological and immunological determinants of dengue epidemics. Proc Natl Acad Sci USA 2006;103:11802–11807.
  89. Adams B, Holmes EC, Zhang C, et al: Cross-protective immunity can account for the alternating epidemic pattern of dengue virus serotypes circulating in Bangkok. Proc Natl Acad Sci USA 2006;103:14234–14239.
  90. Shadrin AS, Marinich IG, Taros LY: Experimental and epidemiological estimation of seasonal and climato-geographical features of non-specific resistance of the organism to influenza. J Hyg Epidemiol Microbiol Immunol 1977;21:155–161.
  91. Bilbo SD, Nelson RJ: Melatonin regulates energy balance and attenuates fever in Siberian hamsters. Endocrinology 2002;143:2527–2533.
  92. Wen JC, Dhabhar FS, Prendergast BJ: Pineal-dependent and -independent effects of photoperiod on immune function in Siberian hamsters (Phodopus sungorus). Horm Behav 2007;51:31–39.
  93. Mersch PP, Middendorp HM, Bouhuys AL, et al: Seasonal affective disorder and latitude: a review of the literature. J Affect Disord 1999;53:35–48.
  94. Srinivasan V, Smits M, Spence W, et al: Melatonin in mood disorders. World J Biol Psychiatry 2006;7:138–151.
  95. Pandi-Perumal SR, Srinivasan V, Cardinali DP, et al: Could agomelatine be the ideal antidepressant? Expert Rev Neurother 2006;6:1595–1608.
  96. Pjrek E, Winkler D, Konstantinidis A, et al: Agomelatine in the treatment of seasonal affective disorder. Psychopharmacology (Berl) 2007;190:575–579.
  97. Leu SJ, Shiah IS, Yatham LN, et al: Immune-inflammatory markers in patients with seasonal affective disorder: effects of light therapy. J Affect Disord 2001;63:27–34.
  98. Esquifino AI, Pandi-Perumal SR, Cardinali DP: Circadian organization of the immune response: a role for melatonin. Clin Appl Immunol Rev 2004;4:423–433.
  99. Iikuni N, Nakajima A, Inoue E, et al: What’s in season for rheumatoid arthritis patients? Seasonal fluctuations in disease activity. Rheumatology (Oxford) 2007;46:846–848.
  100. Maestroni GJ, Sulli A, Pizzorni C, et al: Melatonin in rheumatoid arthritis: a disease-promoting and modulating hormone? Clin Exp Rheumatol 2002;20:872–873.
  101. Sulli A, Maestroni GJ, Villaggio B, et al: Melatonin serum levels in rheumatoid arthritis. Ann NY Acad Sci 2002;966:276–283.
  102. Maestroni GJ, Cardinali DP, Esquifino AI, et al: Does melatonin play a disease-promoting role in rheumatoid arthritis? J Neuroimmunol 2005;158:106–111.
  103. Cutolo M, Maestroni GJ, Otsa K, et al: Circadian melatonin and cortisol levels in rheumatoid arthritis patients in winter time: a north and south Europe comparison. Ann Rheum Dis 2005;64:212–216.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50