The immunotherapeutic potential of melatonin

Abstract

The interaction between the brain and the immune system is essential for the adaptive response of an organism against environmental challenges. In this context, the pineal neurohormone melatonin (MEL) plays an important role. T-helper cells express G-protein coupled cell membrane MEL receptors and, perhaps, MEL nuclear receptors. Activation of MEL receptors enhances the release of T-helper cell Type 1 (Th1) cytokines, such as gamma-interferon (gamma-IFN) and IL-2, as well as of novel opioid cytokines. MEL has been reported also to enhance the production of IL-1, IL-6 and IL-12 in human monocytes. These mediators may counteract stress-induced immunodepression and other secondary immunodeficiencies and protect mice against lethal viral encephalitis, bacterial diseases and septic shock. Therefore, MEL has interesting immunotherapeutic potential in both viral and bacterial infections. MEL may also influence haemopoiesis either by stimulating haemopoietic cytokines, including opioids, or by directly affecting specific progenitor cells such as pre-B cells, monocytes and NK cells. MEL may thus be used to stimulate the immune response during viral and bacterial infections as well as to strengthen the immune reactivity as a prophylactic procedure. In both mice and cancer patients, the haemopoietic effect of MEL may diminish the toxicity associated with common chemotherapeutic protocols. Through its pro-inflammatory action, MEL may play an adverse role in autoimmune diseases. Rheumatoid arthritis patients have increased nocturnal plasma levels of MEL and their synovial macrophages respond to MEL with an increased production of IL-12 and nitric oxide (NO). In these patients, inhibition of MEL synthesis or use of MEL antagonists might have a therapeutic effect. In other diseases such as multiple sclerosis the role of MEL is controversial. However, the correct therapeutic use of MEL or MEL antagonists should be based on a complete understanding of their mechanism of action. It is not yet clear whether MEL acts only on Th1 cells or also on T-helper Type 2 cells (Th2). This is an important point as the Th1/Th2 balance is of crucial importance in the immune system homeostasis. Furthermore, MEL being the endocrine messenger of darkness, its endogenous synthesis depends on the photoperiod and shows seasonal variations. Similarly, the pharmacological effects of MEL might also be season-dependent. No information is available concerning this point. Therefore, studies are needed to investigate whether the immunotherapeutic effect of MEL changes with the alternating seasons.

Generation of the Melatonin Endocrine Message in Mammals: A Review of the Complex Regulation of Melatonin Synthesis by Norepinephrine, Peptides, and Other Pineal Transmitters

“…Effects of Melatonin on the Immune System. Earlier studies reporting that pinealectomized rats displayed a structurally modified thymus and that MEL treatment or pineal grafting prevented thymic involution in very old mice led to the concept that MEL could affect the immune system (see Provinciali et al, 1996;Liebmann et al, 1997;Reiter et al, 2000a;Maestroni, 2001 for reviews). In vivo, high exogenous doses of MEL show a general stimulation of the immune system.…”

Melatonin: reducing the toxicity and increasing the efficacy of drugs

“…Of signi® cance to the current review is that in all species where it has been measured, melatonin levels wane with increasing age such that, in the elderly, melatonin concentrations in the blood are only a fraction of those in the young (Reiter 1992). Functionally, melatonin has been linked to the regulation of seasonal reproduction (Reiter 1980), strengthening of circadian rhythms (Arendt 1988), stimulation of the immune system (Guerrero & Reiter 1992, 2002Maestroni 2001), inhibition of cancer initiation (Reiter 1999 ;Karbownik & Reiter 2000) and tumour growth (Blask et al 1991 ;Sauer et al 2001) and sleep processes (Gar® nkel et al 1995 ;Dijk & Cajochen 1997). That melatonin functions as a powerful free radical scavenger and antioxidant was only uncovered in the last decade Tan et al 1993 ;Hardeland et al 1995 ;Reiter et al , 2002a.…”

Oncostatic effects of the indole melatonin and expression of its cytosolic and nuclear receptors in cultured human melanoma cell lines

“…Melatonin acts as a hormone (1,2), receptor independent autocrine and paracrine antioxidant (3,4), direct radical scavenger (3,5), immunomodulator (6), antiaging factor (7,8) and anticarcinogen (9) depending on the concentrations (10). Increasing evidence in the field suggests that melatonin acts at many extrapineal sites such as the gastrointestinal tract (11,12), the blood cell system (13), the retina (14), the bone marrow (15,16) and the skin (17)(18)(19)(20)(21)(22).…”