Melatonin: a pleiotropic molecule regulating inflammation

TL;DR: The interesting timing of pro- and anti-inflammatory effects, such as those affecting lipoxygenase activity, suggests that melatonin might promote early phases of inflammation on one hand and contribute to its attenuation on the other hand, in order to avoid complications of chronic inflammation.

About: This article is published in Biochemical Pharmacology.The article was published on 2010-12-15 and is currently open access. It has received 298 citations till now. The article focuses on the topics: Melatonin & Pineal gland.

Summary

1. Introduction

• Acute and chronic inflammation are essential to restore homeostasis [1, 2] .
• The mechanisms by which activated leukocytes fight germs and tumor cells or eliminate tissue debris in the inflamed area, lead to production of oxidants and/or of cytotoxic cytokines [2, 3] .
• It is crucial to investigate novel pharmacological approaches that allow to reduce pathologic chronic inflammation without impairing the physiological inflammatory response, since many synthetic anti-inflammatory agents generate considerable side effects.
• Endogenous molecules may be exogenously supplemented, thus increasing overall body levels, and changing timing or localization within the body with respect to their endogenous production.
• Melatonin is very attractive from this point of view as it may act as a regulator of the inflammatory cell compartment with a potent anti-oxidant potential able to reduce the oxidative environment of chronic inflammation and to regulate leukocyte function and number [6, 7] .

2. Melatonin synthesis and its targets

• Melatonin (N-acetyl-5-methoxytryptamine) is derived from tryptophan via enzymatic conversion reactions and is mainly produced by the pineal gland.
• Melatonin plasma concentration varies according to a circadian cycle and this cyclic production determines the periodic effects at a systemic level [8] .
• They belong to the RZR/ROR nuclear hormone receptor family; melatonin binds with high affinity to RZR-beta [27, 28] .
• Additional binding to intracellular targets in the micromolar range, such as the enzymes hydroquinone [31] and calmodulin [32] have been reported.
• In vivo studies with pinealectomized animals [44] allow to discriminate between hormonal and paracrine responses, whereas the study of melatonin synthesis and functions in cultured non-pineal cells [6] provides information of the autocrine effects of melatonin.

3. Neuro-endocrine melatonin: systemic effects of pineal melatonin on immune system

• It is an established notion that the nervous and endocrine systems can interact with the immune system in order to modulate its function [46] ; indeed, many neurotransmitters, neuroendocrine factors and hormones can alter immune function [47] .
• Furthermore, it was demonstrated that melatonin controls diurnal and seasonal rhythms of leukocyte proliferation [51] , of cytokine production [44, 45] and NK cell activity [52] in mammalian bone marrow cells.
• As the melatonin-dependent effects of pinealectomy on the immune response appear to be partial, this further indicates that other compartments can overcome or contribute to immunomodulatory effects triggered by melatonin.
• Accordingly melatonin may act as a paracrine or autocrine regulator in leukocyte communication independent of the pineal gland.
• Indeed Jurkat T cells produce interleukine-2 (IL-2) as a result of endogenous melatonin signaling and Lardone et al. demonstrated that IL-2 production is hampered by specifically inhibiting melatonin signaling by the MT1/MT2 antagonist luzindole [55] .

5. Effect of exogenous melatonin on inflammatory parameters

• The potential use of melatonin as a pharmaceutical agent derives from numerous in vitro studies where melatonin doses exceeding the nocturnal plasma levels are required to exert clear effects.
• At supra-physiological concentrations, melatonin induces T-cell proliferation and upregulation of pro-inflammatory cytokines [43, 57] .
• Exogenous melatonin administration increases the proliferative response of rat lymphocytes [58] , increases the number of NK cells [59, 60] , stimulates the pro-inflammatory cytokines IL-1 and TNF- [61, 62] and enhances phagocytosis [63] .
• In some systems, the modulation of apoptosis requires high melatonin doses [23, 24] .
• Whether or not these effects have a physiological significance, occurring as a paracrine or autocrine response, i.e., in microenvironments with an elevated melatonin concentration like in the bone marrow, is presently investigated.

6. Melatonin, ROS and inflammation

• Oxidative stress can be defined as the imbalance between cellular oxidant species like reactive oxygen species (ROS) production and antioxidant potential.
• Oxidative phenomena play a key role in signaling and management of the initial phase of inflammation.
• Activated neutrophils generate an oxidative burst that directs toxicity towards invading microbes [68] ; ROS generation in the damaged tissue produce a concentration gradient that directs leukocyte recruitment to the site of tissue injury [69] .
• Thus, ROS can promote and drive the inflammatory response in various tissues and can stimulate the signaling pathways triggered by inflammatory conditions [74] .
• Both effects allow melatonin to reduce the extent of ROS, improving oxidative related pathologies such as hypertension [81] , atherosclerosis [82] , cancer [83] , ischemia [84] or neurodegenerative diseases [85] .

7. Effects of melatonin on the arachidonic acid metabolism

• After experimental inflammation induction in vivo and ex vivo, melatonin was shown to prevent or reduce the inflammatory-derived activation of PLA2 [88] , LOX [89] and COX [90] .
• Arachidonic acid then activates 5-LOX triggering production of endogenous monohydroxy-eicosatetraenoic acids [34] .
• The authors can conclude that the stimulation by melatonin of different targets produces different effects, altogether suggesting a sophisticated regulation.
• The activation of 5-LOX and PLA2 activity by melatonin is a transient phenomenon and extinguishes within 2-3 hrs, possibly because of the down-regulation of either 5-LOX or PLA2.
• Thus, melatonin-related down-regulation of NOS could contribute to melatonin"s prevention of inflammation.

8. Role of melatonin in leukocyte survival or apoptosis

• Leukocytes have to perform briefly but efficiently in an oxidative environment that may cause mutations or cell death.
• The mechanisms of the anti-apoptotic action of melatonin in leukocytes have been investigated.
• Oxidative alterations cause Bax disulfide dimerization, and the resulting conformational changes are sufficient for its translocation to mitochondria independently of apoptosis [116] .
• The inhibition of Bax activation may be due to melatonin's anti-oxidant ability, and/or to the simultaneous re-localization of Bcl-2 [108] to mitochondria, thus co-localizing with (and sequestering) Bax.

9. Role of melatonin in maintaining and restoring human health

• Melatonin controls the onset and progression of many human pathological states by multiple mechanisms asdescribed by studies reporting effects of clinical trials.
• Indeed, a mathematical model validated by experimental data and clinical observations, demonstrates the interplay between inflammation and circadian rhythms [117] .
• In critically ill patients, sources of oxidative stress include the mitochondrial respiratory electron transport chain [131] , the respiratory burst associated with neutrophil activation [68] , and arachidonic acid metabolism [132] .
• Melatonin prevents multiple organ failure, circulatory failure, and mitochondrial damage in model of experimental sepsis [137] , and reduces mortality in septic children together with lipid peroxidation as an index of inflammation [138] .
• Altogether, these features make of melatonin a potential therapeutic tool to improve human health.

10. Conclusions and perspectives

• Commonly used anti-inflammatory agents hardy distinguish between physiological and pathological inflammation; the indiscriminate use of anti-inflammatory agents can lead to a deregulation of the inflammatory response, with the risk to fail to fight pathogens or injuries.
• The differential pro-and anti-inflammatory roles of melatonin might promote, regulate, and counteract inflammation simultaneously.
• Freshly explanted blood monocytes require LOX-derived signals and also ROS to maximize in vitro activation and viability, two events that require the over-expression of Bcl-2 [70] .
• It has been long debated that melatonin in some instances may exert a pro-apoptotic role [106] ; the mechanisms and rationale of this effect are unclear.
• This includes a reduction of oxidative damage in the injured tissue as well as the inhibition of pro-inflammatory mediators; break the vicious cycle of oxidation/leukocyte recruitment, and promoting leukocyte apoptosis .

Frequently asked questions

Q1. What is the role of melatonin in the development of many diseases?

Alterations of circadian rhythms implying variations of the 24-h light/dark cycle, play a critical role in the development and progression of many diseases. 

Q2. What is the role of melatonin in preventing oxidative stress?

melatonin plays an important role in activating anti-oxidant defenses such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GSH-Rd) and glucose-6phosphate dehydrogenase (G6PD) [79, 80]. 

Q3. What are the contributions mentioned in the paper "Melatonin: a pleiotropic molecule regulating inflammation" ?

Radogna et al. this paper analyzed the anti-oxidant effects of melatonin on its ability to alter production of pro-inflammatory molecules in vivo and in vitro. 

Q4. What is the role of melatonin in the immune system?

At supra-physiological concentrations, melatonin induces T-cell proliferation and upregulation of pro-inflammatory cytokines [43, 57] . 

Q5. What is the definition of oxidative stress?

Oxidative stress can be defined as the imbalance between cellular oxidant species likereactive oxygen species (ROS) production and antioxidant potential. 

Q6. What is the effect of melatonin on inflammatory cells?

After experimental inflammation induction in vivo and ex vivo, melatonin was shown to prevent or reduce the inflammatory-derived activation of PLA2 [88] , LOX [89] and COX [90]. 

Q7. What is the effect of pinealectomy on the immune system?

It was described that the removal of the pineal gland causes partial (and transient) impairment of immune response in rats [44, 53, 54]; moreover, NK activity and IL-2 production were described to be reduced in rats after pinealectomy [44]. 

Q8. What is the role of melatonin in the development of CF?

In a randomized double-blind, placebo-controlled study [130], melatonin was shown to improve sleep efficiency and sleep latency [130] in cystic fibrosis (CF) patients, a chronic progressive disorder characterized by repeated episodes of respiratory distress and sleep disturbances [130]. 

Q9. What is the role of melatonin in reducing oxidative stress?

Administration of melatonin to humans and animals at both physiological and pharmacological concentrations is essentially non-toxic; it can be easily synthesized in a pharmacologically pure form or extracted by natural sources; it possesses outstanding versatility in reducing oxidative stress and inflammation. 

Q10. What is the role of melatonin in the development of apoptos?

This regulation allows melatonin to coordinate circadian rhythms, including the sleep-wake cycle, thus possessing a beneficial and therapeutic effect as demonstrated by the reports of clinical trials with administration of melatonin [118]. 

Q11. What is the role of melatonin in preventing apoptosis?

the majority of reports indicate that the anti-apoptotic of melatonin occurs by acting on the abundance of the two main members of the Bcl-2 family, namely the pro-apoptotic Bax and the anti-apoptotic Bcl-2 proteins [108]. 

Q12. What is the role of melatonin in the regulation of leukocytes?

this review will cover the effects that melatonin exerts on the abundance of leukocytes via alteration of their proliferation and apoptosis. 

Q13. What is the role of melatonin in the regulation of inflammatory responses?

The authors analyze here data describing the possible modulation of inflammatory functions with afocus on the anti-oxidant effects of melatonin on its ability to alter production of pro-inflammatory molecules in vivo and in vitro.