Abstract
Tuberculosis (TB) is the second most frequent cause of death in the world, after AIDS. Delay in diagnosing TB is an important worldwide problem. It seriously threatens public health. Cell-mediated immune responses play an important role in the pathogenesis of TB infection. The course of Mycobacterium tuberculosis (MTb) infection is regulated by two distinct T cell cytokine patterns. Melatonin is a biomolecule (mainly secreted by the pineal gland) with free radical scavenging, antioxidant and immunoregulatory properties. Melatonin has both its direct and indirect immunomodulatory effects on the immune system. In this study, we measured plasma melatonin and urine 6-hydroxy melatonin sulphate (6-HMS) concentrations in patients with newly diagnosed TB for the purpose of investigating whether there was a relationship between their levels and MTb infection. Thirty-one newly diagnosed patients presenting with active TB and 31 healthy subjects as the control group were included in this study. Blood and 24-h urine samples were collected from all individuals. Plasma melatonin levels and urine 6-HMS were measured. Our results show that in patients with TB, mean melatonin and 6-HMS concentrations were significantly lower than in the control subjects (p = 0.037, p < 0.001, respectively). We believe that the treatment of TB patients with melatonin might result in a wide range of health benefits including improved quality of life and reduced severity of infection in these patients. Supplementation with melatonin may be considered as an adjunctive therapy to classic treatment of pulmonary TB, especially during the acute phase of infection.
Similar content being viewed by others
References
Malik, Z.A., G.M. Denning, and D.J. Kusner. 2000. Inhibition of Ca(2+) signaling by Mycobacterium tuberculosis is associated with reduced phagosome-lysosome fusion and increased survival within human macrophages. The Journal of Experimental Medicine 191: 287–302.
Rocha-Ramirez, L.M., I. Estrada-Garcia, L.M. Lopez-Marin, E. Segura-Salinas, P. Mendez-Aragon, D. Van Soolingen, et al. 2008. Mycobacterium tuberculosis lipids regulate cytokines, TLR-2/4 and MHC class II expression in human macrophages. Tuberculosis (Edinburgh, Scotland) 88: 212–220.
del Corral, H., S.C. Paris, N.D. Marin, D.M. Marin, L. Lopez, H.M. Henao, et al. 2009. IFNgamma response to Mycobacterium tuberculosis, risk of infection and disease in household contacts of tuberculosis patients in Colombia. PLoS One 4: e8257.
Caws, M., G. Thwaites, S. Dunstan, T.R. Hawn, N.T. Lan, N.T. Thuong, et al. 2008. The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis. PLoS Pathogens 4: e1000034.
Chan, J., and J. Flynn. 2004. The immunological aspects of latency in tuberculosis. Clinical Immunology 110: 2–12.
Antas, P.R., F.L. Cardoso, K.C. Pereira, K.L. Franken, K.S. Cunha, P. Klatser, et al. 2005. T cell immune responses to mycobacterial antigens in Brazilian tuberculosis patients and controls. Transactions of the Royal Society of Tropical Medicine and Hygiene 99: 699–707.
Tufariello, J.M., J. Chan, and J.L. Flynn. 2003. Latent tuberculosis: mechanisms of host and bacillus that contribute to persistent infection. The Lancet Infectious Diseases 3: 578–590.
Reiter, R.J. 1991. Melatonin: the chemical expression of darkness. Molecular and Cellular Endocrinology 79: C153–C158.
Reiter, R.J., D.X. Tan, E. Sanchez-Barcelo, M.D. Mediavilla, E. Gitto, and A. Korkmaz. 2011. Circadian mechanisms in the regulation of melatonin synthesis: disruption with light at night and the pathophysiological consequences. Journal of Experimental and Integrative Medicine 1: 13–22.
Reiter, R.J. 1993. The melatonin rhythm: both a clock and a calendar. Experientia 49: 654–664.
Reiter, R.J., S.D. Paredes, A. Korkmaz, L.C. Manchester, and D.X. Tan. 2008. Melatonin in relation to the “strong” and “weak” versions of the free radical theory of aging. Advances in Medical Sciences 53: 119–129.
Poeggeler, B. 2005. Melatonin, aging, and age-related diseases: perspectives for prevention, intervention, and therapy. Endocrine 27: 201–212.
Reiter, R.J., D.X. Tan, and L. Fuentes-Broto. 2010. Melatonin: a multitasking molecule. Progress in Brain Research 181: 127–151.
Macchi, M.M., and J.N. Bruce. 2004. Human pineal physiology and functional significance of melatonin. Frontiers in Neuroendocrinology 25: 177–195.
Srinivasan, V., D.P. Cardinali, S.R. Pandi-Perumal, and G.M. Brown. 2011. Melatonin agonists for treatment of sleep and depressive disorders. Journal of Experimental and Integrative Medicine 1: 149–158.
Terron, M.P., J. Delgado, S.D. Paredes, C. Barriga, R.J. Reiter, and A.B. Rodriguez. 2009. Effect of melatonin and tryptophan on humoral immunity in young and old ringdoves (Streptopelia risoria). Experimental Gerontology 44: 653–658.
Santello, F.H., E.O. Frare, C.D. dos Santos, and L.C. Caetano. 2008. Alonso Toldo MP, do Prado JC, Jr. Suppressive action of melatonin on the TH-2 immune response in rats infected with Trypanosoma cruzi. Journal of Pineal Research 45: 291–296.
Arendt, J., C. Bojkowski, C. Franey, J. Wright, and V. Marks. 1985. Immunoassay of 6-hydroxymelatonin sulfate in human plasma and urine: abolition of the urinary 24-hour rhythm with atenolol. Journal of Clinical Endocrinology and Metabolism 60: 1166–1173.
Wisniewska-Jarosinska, M., J. Chojnacki, S. Konturek, T. Brzozowski, J. Smigielski, and C. Chojnacki. 2010. Evaluation of urinary 6-hydroxymelatonin sulphate excretion in women at different age with irritable bowel syndrome. Journal of Physiology and Pharmacology 61: 295–300.
Ozkan E, Yaman H, Cakir E, Aydin I, Oztosun M, Agilli M, et al. 2012. The measurement of plasma melatonin levels by high performance liquid chromatography. Journal of Experimental and Integrative Medicine 2: 85–88.
Guerrero, J.M., and R.J. Reiter. 2002. Melatonin-immune system relationships. Current Topics in Medicinal Chemistry 2: 167–179.
Lissoni, P., F. Rovelli, F. Brivio, O. Brivio, and L. Fumagalli. 1998. 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. Natural Immunity 16: 1–5.
Maestroni, G.J., A. Conti, and W. Pierpaoli. 1986. Role of the pineal gland in immunity. Circadian synthesis and release of melatonin modulates the antibody response and antagonizes the immunosuppressive effect of corticosterone. Journal of Neuroimmunology 13: 19–30.
Jankovic, B.D., K. Isakovic, and S. Petrovic. 1970. Effect of pinealectomy on immune reactions in the rat. Immunology 18: 1–6.
Carrillo-Vico, A., J.M. Guerrero, P.J. Lardone, and R.J. Reiter. 2005. A review of the multiple actions of melatonin on the immune system. Endocrine 27: 189–200.
Caroleo, M.C., D. Frasca, G. Nistico, and G. Doria. 1992. Melatonin as immunomodulator in immunodeficient mice. Immunopharmacology 23: 81–89.
Garcia-Maurino, S., M.G. Gonzalez-Haba, J.R. Calvo, M. Rafii-El-Idrissi, V. Sanchez-Margalet, R. Goberna, et al. 1997. 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. Journal of Immunology 159: 574–581.
Santello, F.H. 2009. Del Vecchio Filipin M, Caetano LC, Brazao V, Caetano LN, Dos Santos CD, et al. Influence of melatonin therapy and orchiectomy on T cell subsets in male Wistar rats infected with Trypanosoma cruzi. Journal of Pineal Research 47: 271–276.
Terron Mdel, P., S.D. Paredes, C. Barriga, E. Ortega, R.J. Reiter, and A.B. Rodriguez. 2005. Oral administration of melatonin to old ring doves (Streptopelia risoria) increases plasma levels of melatonin and heterophil phagocytic activity. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 60: 44–50.
Rodriguez, A.B., and R.W. Lea. 1994. Effect of pinealectomy upon the nonspecific immune response of the ring-dove (Streptopelia risoria). Journal of Pineal Research 16: 159–166.
Siopes, T.D., and H.A. Underwood. 2008. Diurnal variation in the cellular and humoral immune responses of Japanese quail: role of melatonin. General and Comparative Endocrinology 158: 245–249.
Raghavendra, V., V. Singh, S.K. Kulkarni, and J.N. Agrewala. 2001. Melatonin enhances Th2 cell mediated immune responses: lack of sensitivity to reversal by naltrexone or benzodiazepine receptor antagonists. Molecular and Cellular Biochemistry 221: 57–62.
Skwarlo-Sonta, K. 2002. Melatonin in immunity: comparative aspects. Neuro Endocrinology Letters 23(Suppl 1): 61–66.
Rai, S., and C. Haldar. 2003. Pineal control of immune status and hematological changes in blood and bone marrow of male squirrels (Funambulus pennanti) during their reproductively active phase. Comparative Biochemistry and Physiology—Part C: Toxicology & Pharmacology 136: 319–328.
Nagayama, N., and M. Ohmori. 2006. Seasonality in various forms of tuberculosis. The International Journal of Tuberculosis and Lung Disease 10: 1117–1122.
Thorpe, L.E., T.R. Frieden, K.F. Laserson, C. Wells, and G.R. Khatri. 2004. Seasonality of tuberculosis in India: is it real and what does it tell us? Lancet 364: 1613–1614.
Singh, S.S., and C. Haldar. 2007. Peripheral melatonin modulates seasonal immunity and reproduction of Indian tropical male bird Perdicula asiatica. Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology 146: 446–450.
Meylan, P.R., D.D. Richman, and R.S. Kornbluth. 1992. Reduced intracellular growth of mycobacteria in human macrophages cultivated at physiologic oxygen pressure. American Review of Respiratory Disease 145: 947–953.
Oberley-Deegan, R.E., B.W. Rebits, M.R. Weaver, A.K. Tollefson, X. Bai, M. McGibney, et al. 2010. An oxidative environment promotes growth of Mycobacterium abscessus. Free Radical Biology & Medicine 49: 1666–1673.
Hardeland, R., D.X. Tan, and R.J. Reiter. 2009. Kynuramines, metabolites of melatonin and other indoles: the resurrection of an almost forgotten class of biogenic amines. Journal of Pineal Research 47: 109–126.
Allegra, M., R.J. Reiter, D.X. Tan, C. Gentile, L. Tesoriere, and M.A. Livrea. 2003. The chemistry of melatonin’s interaction with reactive species. Journal of Pineal Research 34: 1–10.
Andersen, P., and I. Heron. 1993. Specificity of a protective memory immune response against Mycobacterium tuberculosis. Infection and Immunity 61: 844–851.
Condos, R., W.N. Rom, Y.M. Liu, and N.W. Schluger. 1998. Local immune responses correlate with presentation and outcome in tuberculosis. American Journal of Respiratory and Critical Care Medicine 157: 729–735.
Budak, F., E.K. Uzaslan, S. Cangur, G. Goral, and H.B. Oral. 2008. Increased pleural soluble fas ligand (sFasL) levels in tuberculosis pleurisy and its relation with T-helper type 1 cytokines. Lung 186: 337–343.
Carrillo-Vico, A., A. Garcia-Perganeda, L. Naji, J.R. Calvo, M.P. Romero, and J.M. Guerrero. 2003. Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system. Cellular and Molecular Life Sciences 60: 2272–2278.
Cutolo, M., A. Sulli, C. Pizzorni, M.E. Secchi, S. Soldano, B. Seriolo, et al. 2006. Circadian rhythms: glucocorticoids and arthritis. Annals of the New York Academy of Sciences 1069: 289–299.
Reiter, R.J. 2003. Melatonin: clinical relevance. Best Practice & Research. Clinical Endocrinology & Metabolism 17: 273–285.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ozkan, E., Yaman, H., Cakir, E. et al. Plasma Melatonin and Urinary 6-Hydroxymelatonin Levels in Patients with Pulmonary Tuberculosis. Inflammation 35, 1429–1434 (2012). https://doi.org/10.1007/s10753-012-9456-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10753-012-9456-3