Mechanisms of interaction of melatonin with lymphocytes

Main Article Content

Elena M. Kuklina
Natalia S. Glebezdina

Abstract

Melatonin is an indoleamine synthesized from the essential amino acid tryptophan. At the system level, it is produced mainly by the pineal gland, and at the local level, by most organs and tissues, including the gastrointestinal tract, liver, kidneys, lungs, skin, tissues of the reproductive system, and many others. The hormone regulates a wide range of biological reactions in health and diseases, and has a pronounced antioxidant, anti-inflammatory and antitumor activity. Along with this, melatonin is an effective regulator of the immune system, however, the data available to date on the problem are extremely contradictory, especially for the main effectors of adaptive immunity - T-lymphocytes. On the one hand, under physiological conditions or under immunodeficiency conditions, the effects of melatonin are usually stimulatory: it enhances the proliferative response of T- and B-lymphocytes, increases the production of Th1-cytokines, and inhibits apoptosis of lymphocytes induced by various stimuli. On the other hand, there are no fewer works demonstrating the immunosuppressive activity of melatonin, in particular, suppression of the production of pro-inflammatory cytokines.  The resolution of these contradictions is the goal of this review. At the same time, the work focuses on two fundamental points. First, the main part of immunostimulating effects was obtained in experiments in vitro, while immunosuppressive effects were obtained in vivo, and since melatonin controls the synthesis of a number of other hormones of the hypothalamic-pituitary-adrenal and / or gonadal axes, many of which are effective immunomodulators themselves, it direct effects in vivo can be mediated and offset by other hormones. Second, lymphocytes express three high-affinity melatonin receptors: two membrane receptors, MT1 and MT2, and a nuclear one, RORα, as well as a number of low-specific targets, all with varying affinities for melatonin. Binding of different receptors apparently triggers different signaling mechanisms. Accordingly, physiological, pathological and pharmacological concentrations of melatonin can have different immunomodulating effects, and when evaluating the effect of melatonin on the immune system, it is important to correlate the hormone concentrations with the state of the receptor apparatus of the cells under study.

Article Details

How to Cite
Kuklina Е. М., & Glebezdina Н. С. (2023). Mechanisms of interaction of melatonin with lymphocytes. Bulletin of Perm University. Biology, (2), 195–204. https://doi.org/10.17072/1994-9952-2023-2-195-204
Section
Иммунология
Author Biographies

Elena M. Kuklina, Perm Federal Research Center, Institute of Ecology and Genetics of Microorganisms, Ural Branch of the Russian Academy of Sciences, Perm, Russia

Doctor of biology, leading researcher of laboratory of immunoregulation

Natalia S. Glebezdina, Perm Federal Research Center, Institute of Ecology and Genetics of Microorganisms, Ural Branch of the RAS, Perm, Russia

Candidate of biology, junior researcher of laboratory of immunoregulation

References

Глебездина Н.С. и др. Молекулярные механизмы контроля дифференцировки регуляторных Т-лимфоцитов экзогенным мелатонином // Доклады Академии наук. 2019a. Т. 484, № 2. С. 224–227.

Глебездина Н.С. и др. Вклад разных типов мелатониновых рецепторов в гормон-зависимую регу-ляцию дифференцировки Т-лимфоцитов, продуцирующих IL-17 (Th17) // Российский иммунологический журнал. 2019b. Т. 13, № 2. С. 751–753.

Куклина Е.М., Глебездина Н.С., Некрасова И.В. Роль мелатонина в контроле дифференцировки Т-лимфоцитов, продуцирующих интерлейкин-17 (Th17) // Бюллетень экспериментальной биологии и меди-цины. 2015. Т. 160, № 11. С. 604–607.

Alvarez-Sanchez N. et al. Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance // Brain Behav Immun. 2015. Vol. 50. P. 101–114.

Arias J. et al. Effect of melatonin on lymphocyte proliferation and production of interleukin-2 (IL-2) and interleukin-1 beta (IL-1 beta) in mice splenocytes // Invest. Clin. 2003. Vol. 44, № 1. P. 41–50.

Calamini B. et al. Kinetic, thermodynamic and X-ray structural insights into the interaction of melatonin and analogues with quinone reductase 2 // Biochem. J. 2008. Vol. 413(1). P. 81–91.

Calvo J.R., Gonzalez-Yanes C., Maldonado M. D. The role of melatonin in the cells of the innate immuni-ty: a review // J. Pineal. Res. 2013. Vol. 55, № 2. P. 103−120.

Cardinali D.P et al. Melatonin and the metabolic syndrome: physiopathologic and therapeutical implica-tions // Neuroendocrinology. 2011. Vol. 93, № 3. P. 133−142.

Carrillo-Vico A. et al. Evidence of mle synthesis by human lymphocytes and its physiological significance: possible role as intracine, autocrine and/or paracrine substance // FASEB J. 2004. Vol. 18. P. 537–539.

Carrillo-Vico A., Lardone P.J., Naji L. Beneficial pleiotropic actions of melatonin in an experimental model of septic shock in mice: Regulation of pro-/ anti-inflammatory cytokine network, protection against oxi-dative damage and anti-apoptotic effects // J. Pineal. Res. 2005. Vol. 39. P. 400–408.

Carrillo-Vico A. et al. Melatonin: buffering the immune system // Int. J. Mol. Sci. 2013. Vol. 14, № 4. P. 8638−8683.

Chen F. et al. Effect of melatonin on monochromatic light-induced T-lymphocyte proliferation in the thymus of chickens // J. Photochem. Photobiol B. 2016. Vol. 161. P. 9–16.

Comai S., Gobbi G. Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsy-chiatric diseases: a novel target in psychopharmacology // J. Psychiatry Neurosci. 2014. Vol. 39. P. 6–21.

Cutando A. et al. Role of melatonin in cancer treatment // Anticancer Res. 2012. Vol. 32, № 7. P. 2747−2753.

Ding S. et al. Melatonin stabilizes rupture-prone vulnerable plaques via regulating macrophage polariza-tion in a nuclear circadian receptor RORα-dependent manner // J. Pineal. Res. 2019. Vol. 67. P. e12581.

Drazen D.L. et al. In vitro melatonin treatment enhances splenocyte proliferation in prairie voles // J. Pin-eal. Res. 2000. Vol. 28, № 1. P. 34−40.

Du J. et al. Isoform-Specific Inhibition of RORα-Mediated Transcriptional Activation by Human FOXP3 // J. Immunol. 2008. Vol. 180, № 7. P. 4785–4792.

Dubocovich M.L., Markowska M. Functional MT1 and MT2 melatonin receptors in mammals // Endo-crine. 2005. Vol. 27. P. 101–110.

Ekmekcioglu C. Melatonin receptors in humans: biological role and clinical relevance // Biomed. Phar-macother. 2006. Vol. 60, № 3. P. 97–108.

Emet M. et al. A Review of Melatonin, Its Receptors and Drugs // The Eurasian Journal of Medicine. 2016. Vol. 48 (2). P. 135–141.

Espino J. et al. Protective effect of melatonin against human leukocyte apoptosis induced by intracellu-lar calcium overload: relation with its antioxidant actions // J. Pineal. Res. 2011. Vol. 51, № 2. P. 195–206.

Espino J., Rodriguez A.B., Pariente J.A. The inhibition of TNF-α-induced leucocyte apoptosis by melato-nin involves membrane receptor MT1/MT2 interaction // J. Pineal. Res. 2013. Vol. 54, № 4. P. 442–452.

Farez M.F. et al. Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses // Cell. 2015. Vol. 162. P. 1338–1352.

Farez M.F. et al. Anti-inflammatory effects of melatonin in multiple sclerosis // Bioessays. 2016. Vol. 38. P. 1016–1026.

Favero G. et al. Melatonin as an Anti-Inflammatory Agent Modulating Inflammasome Activation // Int. J. Endocrinol. 2017. Vol. 2017. P. 1835195.

Ferlazzo N. et al. Is Melatonin the Cornucopia of the 21st Century? // Antioxidants. 2020. Vol. 9, № 11. P. 1088.

Garcia J.A. et al. Disruption of the NF-κB/NLRP3 connection by melatonin requires retinoid-related or-phan receptor-α and blocks the septic response in mice // FASEB J. 2015. Vol. 29. P. 3863–3875.

Garcia-Maurino S. et al. Melatonin enhances IL-2, IL-6, and IFNγ production by human circulating CD4+ cells: a possible nuclear receptor-mediated mechanism involving T helper type 1 lymphocytes and mono-cytes // J. Immunol. 1997. Vol. 159. P. 574–581.

Garcia-Maurino S. Melatonin activates Th1 lymphocytes by increasing IL-12 production // Life Sci. 1999. Vol. 65 P. 2143–2150.

Guerrero J.M., Reiter R.J. Melatonin-immune system relationships // Curr. Top. Med. Chem. 2002. V. 2. P. 167–179.

Gupta S., Haldar C. Physiological crosstalk between melatonin and glucocorticoid receptor modulates t-cell mediated immune responses in a wild tropical rodent, funambulus pennant // J. Steroid. Biochem. Mol. Biol. 2013. Vol. 134. P. 23–36.

Huang H. et al. Melatonin prevents endothelial dysfunction in SLE by activating the nuclear receptor ret-inoic acid-related orphan receptor-α // Int. Immunopharmacol. 2020. Vol. 83. P. 106365.

Johansson L.C. et al. XFEL structures of the human MT2 melatonin receptor reveal the basis of subtype selectivity // Nature. 2019. Vol. 569 (7755). P. 289–292.

Kato K. et al. Neurochemical properties of ramelteon (TAK-375), a selective MT35. 1/MT2 receptor ag-onist // Neuropharmacology. 2005. Vol. 48. P. 301–310.

Kojima H., Muromoto R., Takahashi M. Inhibitory effects of azole-type fungicides on interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ // Toxicol. Appl. Pharmacol. 2012. Vol. 259. P. 338–345.

Kuklina E.M. Melatonin as potential inducer of Th17 cell differentiation // Medical Hypothesis. 2014. Vol. 83. P. 404–406.

Lardone P.J. et al. Melatonin synthesized by Jurkat human leukemic T cell line is implicated in IL-2 pro-duction // J. Cell. Physiol. 2006. Vol. 206. P. 273–279.

Lardone P.J. et al. Blocking of melatonin synthesis and MT(1) receptor impairs the activation of Jurkat T cells // Cell. Mol. Life. Sci. 2010. Vol. 67. P. 3163–3172.

Lardone P.J. et al. Melatonin synthesized by T lymphocytes as a ligand of the retinoic acid-related or-phan receptor // J. Pineal Res. 2011. Vol. 51. P. 454–462.

Leon J. et al. Structure-related inhibition of calmodulin-dependent neuronal nitric-oxide synthase activity by melatonin and synthetic kynurenines // Mol. Pharmacol. 2000. Vol. 58, № 5. P. 967–975.

Li Z. et al. Melatonin inhibits apoptosis in mouse Leydig cells via the retinoic acid-related orphan nuclear receptor α/p53 pathway // Life Sci. 2020. Vol. 246. P. 117431.

Lin L. et al. Melatonin in Alzheimer’s disease // Int. J. Mol. Sci. 2013. Vol. 14. P. 14575−14593.

Ma H. et al. ROR: Nuclear Receptor for Melatonin or Not? // Molecules. 2021. Vol. 26, № 9. P. 2693.

Mahmood D. Pleiotropic Effects of Melatonin // Drug Res (Stuttg). 2019. Vol. 69, № 2. P. 65−74.

Naranjo M.C. et al. Melatonin biosynthesis in the thymus of humans and rats // Cell. Mol. Life Sci. 2007. Vol. 64, № 6. P. 781–790.

NaveenKumar S.K. et al. Melatonin restores neutrophil functions and prevents apoptosis amid dysfunc-tional glutathione redox system // J. Pineal. Res. 2020. Vol. 69, № 3. P. e12676.

Okamoto H.H. et al. Cryo-EM structure of the human MT1-Gi signaling complex // Nat. Struct. Mol Biol. 2021. Vol. 28 (8). P. 694–701.

Pariente R. et al. Participation of MT3 melatonin receptors in the synergistic effect of melatonin on cyto-toxic and apoptotic actions evoked by chemotherapeutics // Cancer Chemother Pharmacol. 2017. Vol. 80, № 5. P. 985–998.

Pozo D. et al. mRNA expression of nuclear receptor RZR/RORa, melatonin membrane receptor MT1, and hydroxindole-O-methyltransferase in different populations of human immune cells // J. Pineal. Res. 2004. Vol. 37. P. 48−54.

Raghavendra V. et al. Melatonin provides signal 3 to unprimed CD4(+) T cells but failed to stimulate LPS primed B cells // Clin. Exp. Immunol. 2001. Vol. 124. P. 414–422.

Ragonda F., Diederich M., Ghibelli L. Melatonin: a pleiotropic molecule regulating inflammation // Bio-chem. Pharmacol. 2010. Vol. 80. P. 1844–1852.

Reppert S.M. et al. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor // Proc. Natl. Acad. Sci. USA. 1995. Vol. 92, № 19. P. 8734–8738.

Reppert S.M., Weaver D.R., Ebisawa T. Cloning and characterization of a mammalian melatonin recep-tor that mediates reproductive and circadian responses // Neuron. 1994 Vol. 13, № 5. P. 1177-1185.

Sanchez-Barcelo E.J. et al. Melatonin-estrogen interactions in breast cancer // J. Pineal. Res. 2005. Vol. 38, № 4. P. 217–222.

Shaji A.V., Kulkarni S.K., Agrewala J.N. Regulation of secretion of IL-4 and IgG1 isotype by melatonin-stimulated ovalbuminspecific T cells // Clin. Exp. Immunol. 1998. Vol. 111. P. 181–185.

Shen S. et al. The role of melatonin in the treatment of type 2 diabetes mellitus and Alzheimer's disease // Int. J. Biol. Sci. 2022. Vol. 18, № 3. P. 983−994.

Slominski A.T. et al. RORα and ROR γ are expressed in human skin and serve as receptors for endoge-nously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D // FASEB J. 2014. Vol. 28. P. 2775–2789.

Spinedi E., Cardinali D.P. Neuroendocrine-Metabolic Dysfunction and Sleep Disturbances in Neuro-degenerative Disorders: Focus on Alzheimer's Disease and Melatonin // Neuroendocrinology. 2019. Vol. 108, № 4. P. 354−364.

Srinivasan V., Cardinali D.P., Srinivasan U.S. Therapeutic potential of melatonin and its analogs in Par-kinson’s disease: focus on sleep and neuroprotection // Ther. Adv. Neurol. Disord. 2011. Vol. 4. P. 297−317.

Stauch B. et al. Structural basis of ligand recognition at the human MT1 melatonin receptor // Nature. 2019. Vol. 569, № 7755. P. 284–288.

Sun H., Gusdon A.M., Qu S. Effects of melatonin on cardiovascular diseases: progress in the past year // Curr. Opin. Lipidol. 2016. Vol. 27, № 4. P. 408−413.

Tan D.X. et al. Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism // Molecules. 2015. Vol. 20, № 10. P. 18886–18906.

Wiesenberg I. et al. Transcriptional activation of the nuclear receptor RZRα by the pineal gland hormone melatonin and dentification of CGP52608 as a synthetic ligand // Nucleic. Acid. Res. 1995. Vol. 23. P. 327–333.

Wu C.C. et al. Melatonin enhances endogenous heme oxygenase-1 and represses immune responses to ameliorate experimental murine membranous nephropathy // J. Pineal. Res. 2012. Vol. 52, № 4. P. 460–469.

Xu L. et al. Melatonin differentially regulates pathological and physiological cardiac hypertrophy: Cru-cial role of circadian nuclear receptor RORα signaling // J. Pineal. Res. 2019. Vol. 67. P. e12579.

Yang X.O. et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR al-pha and ROR gamma // Immunity. 2008. Vol. 28. P. 29–39.

Yoo Y.M. et al. Pharmacological advantages of melatonin in immunosenescence by improving activity of T lymphocytes // J. Biomed. Res. 2016. Vol. 30. P. 314–321.

Zang M. et al. The circadian nuclear receptor RORα negatively regulates cerebral ischemia–reperfusion injury and mediates the neuroprotective effects of melatonin. BBA // Mol. Basis Dis. 2020. Vol. 1866. P. 165890.