Effect of the melatonin nuclear receptor RORα on monochromatic light-induced T-lymphocyte proliferation in chicken thymus.

Present study clarified role of melatonin nuclear receptor RORα in monochromatic light-induced T-lymphocyte proliferation in chicks. Green light elevated plasma melatonin level and organ index, T-lymphocyte proliferation and IL-2 production in thymus, but decreased RORα, p-P65 and p-IκB expressions relative to red light. By contrast, pinealectomy decreased the melatonin content and reversed the stimulatory effect of green light, and resulted in that these thymus parameters were not significantly different among the light-treated groups. Exogenous melatonin supplementation enhanced T-lymphocyte proliferation and IL-2 production in cultured thymocytes. This stimulatory effect of melatonin was reversed by RORα agonist but was enhanced by RORα antagonist. In contrast to RORα antagonist, RORα agonist decreased cytoplasmic P65 level and increased nuclear P65 level. Supplementation with P65 antagonist increased T-lymphocyte proliferation. We conclude that RORα could negatively regulate green light-enhanced T-lymphocyte proliferation in chick thymus by upregulating IκB phosphorylation, which promotes P65 nuclear translocation and NF-κB activation.

Potential role of melatonin in autoimmune diseases.

Autoimmune diseases are a broad spectrum of disorders involved in the imbalance of T-cell subsets, in which interplay or interaction of Th1, Th17 and Tregs are most important, resulting in prolonged inflammation and subsequent tissue damage. Pathogenic Th1 and Th17 cells can secrete signature proinflammatory cytokines, including interferon (IFN)-γ and IL-17, however Tregs can suppress effector cells and dampen a wide spectrum of immune responses. Melatonin (MLT) can regulate the humoral and cellular immune responses, as well as cell proliferation and immune mediators. Treatment with MLT directly interferes with T cell differentiation, controls the balance between pathogenic and regulatory T cells and regulates inflammatory cytokine release. MLT can promote the differentiation of type 1 regulatory T cells via extracellular signal regulated kinase 1/2 (Erk1/2) and retinoic acid-related orphan receptor-α (ROR-α) and suppress the differentiation of Th17 cells via the inhibition of ROR-γt and ROR-α expression through NFIL3. Moreover, MLT inhibits NF-κB signaling pathway to reduce TNF-α and IL-1ß expression, promotes Nrf2 gene and protein expression to reduce oxidative and inflammatory states and regulates Bax and Bcl-2 to reduce apoptosis; all of which alleviate the development of autoimmune diseases. Thus, MLT can serve as a potential new therapeutic target, creating opportunities for the treatment of autoimmune diseases. This review aims to highlight recent advances in the role of MLT in several autoimmune diseases with particular focus given to novel signaling pathways involved in Th17 and Tregs as well as cell proliferation and apoptosis.

Update on melatonin receptors: IUPHAR Review 20.

Melatonin receptors are seven transmembrane-spanning proteins belonging to the GPCR superfamily. In mammals, two melatonin receptor subtypes exist - MT1 and MT2 - encoded by the MTNR1A and MTNR1B genes respectively. The current review provides an update on melatonin receptors by the corresponding subcommittee of the International Union of Basic and Clinical Pharmacology. We will highlight recent developments of melatonin receptor ligands, including radioligands, and give an update on the latest phenotyping results of melatonin receptor knockout mice. The current status and perspectives of the structure of melatonin receptor will be summarized. The physiological importance of melatonin receptor dimers and biologically important and type 2 diabetes-associated genetic variants of melatonin receptors will be discussed. The role of melatonin receptors in physiology and disease will be further exemplified by their functions in the immune system and the CNS. Finally, antioxidant and free radical scavenger properties of melatonin and its relation to melatonin receptors will be critically addressed.

The pineal regulation of the immune system: 40 years since the discovery.

The first observation on the relationship between the pineal gland and the immune system was done by the author of this paper in the late sixties and early seventies of the last century. After neonatal pinealectomy the thymus has been destroyed and wasting disease developed. Since that time a flood of experiments justified the observation and pointed to the prominent role of pineal in the regulation of the immune system. Melatonin, the hormone of the pineal gland stimulates immune processes acting to the immune cells' cytokine production, the haemopoiesis, and immune cell-target cell interactions. Melatonin receptors have been demonstrated and their localization and function were justified. Melatonin production by and melatonin receptors on (and in) the immune cells was proved. Melatonin agonists have been synthesized and the use of melatonin as adjuvant in the therapy of diseases connected to the immune system (cancers included) has been started. The paper summarizes the most important studies and discusses the interrelations of the data. The discussion points to the possibility of packed transport of the pineal hormone by the immune cells and to the adventages of local regulation by this transport.

Melatonin: buffering the immune system.

Melatonin modulates a wide range of physiological functions with pleiotropic effects on the immune system. Despite the large number of reports implicating melatonin as an immunomodulatory compound, it still remains unclear how melatonin regulates immunity. While some authors argue that melatonin is an immunostimulant, many studies have also described anti-inflammatory properties. The data reviewed in this paper support the idea of melatonin as an immune buffer, acting as a stimulant under basal or immunosuppressive conditions or as an anti-inflammatory compound in the presence of exacerbated immune responses, such as acute inflammation. The clinical relevance of the multiple functions of melatonin under different immune conditions, such as infection, autoimmunity, vaccination and immunosenescence, is also reviewed.

Reciprocal interaction between melatonin receptors (Mel(1a), Mel(1b), and Mel(1c)) and androgen receptor (AR) expression in immunoregulation of a seasonally breeding bird, Perdicula asiatica: role of photoperiod.

Light is the major environmental stimulus affecting behaviour and physiology of avian species. Our study elaborates the photoperiodic regulation of melatonin (Mel1a, Mel1b, and Mel1c) and androgen receptor (AR) to elucidate its reciprocal interaction in regulation of general immunity in tropical wild bird, Perdicula asiatica. Effect of different photoperiodic exposures such as continuous light (LL), continuous dark (DD), long days (LD; 16 h light/day), short days (SD; 10h light/day) and normal day length (NDL) was accessed both on cellular and humoral immune parameters like per cent stimulation ratio (%SR), total leukocyte count (TLC), leukocyte count (LC), plasma interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-α), spleen and gonad weight, plasma melatonin, and testosterone level as well as their receptor expression on spleen and testis. Expression of melatonin receptor, Mel1a and Mel1b in spleen was high in SD experiencing bird as compared to LD birds. In all photoperiodic groups, AR expression was upregulated in spleen. In addition, our reverse transcription polymerase chain reaction (RT-PCR) results support differentially localized mRNA Mel1b and Mel1c expression in spleen and testis. In sum, photoperiodically modulated level of melatonin via reciprocal regulation of Mel1a, Mel1b, and Mel1c, and AR in spleen as well as in testis modulates immunity, suggesting a compensatory mechanism between reproduction and immunity in a seasonally breeding bird, P. asiatica.

Pulmonary innate immune response and melatonin receptors in the perinatal stress.

OBJECTIVE: To analyze the cytokines of the innate immune pulmonary response and the capacity for local response to melatonin according to the perinatal stress. METHODS: 49 cases of pediatric autopsies were evaluated, divided according to cause of death, perinatal stress, gestational age, and birth weight. The percentages of IL-6, C-reactive protein (CRP), IL-1ß, TNF-α, and melatonin receptor were evaluated by immunohistochemistry. RESULTS: The IL-6 expression was higher in the children showing chronic stress, anoxia, and infection. The IL-6 expression showed a progressive increase according to the relation between weight and GA. There was no significant difference in the expression of IL-1ß and TNF-α. The CRP expression was higher in the cases showing chronic stress and premature cases. The expression of melatonin receptors was significantly higher in the cases showing chronic stress, being more evident in the cases showing infection. CONCLUSION: The cause of death and the type of stress influence the expression in situ of melatonin and cytokines of the innate immune pulmonary response. The evaluation of IL-6 and CRP may contribute to the understanding of the evolution of neonates with chronic stress. The greater sensitivity of the lung to melatonin in these cases may indicate an attempt at controlling the immunological response, in an attempt to diminish the harmful effects of stress.

Physiological crosstalk between melatonin and glucocorticoid receptor modulates T-cell mediated immune responses in a wild tropical rodent, Funambulus pennanti.

Immunoenhancing attributes of melatonin (Mel) on the immunocompromised state induced by glucocorticoid is well known, but the involvement of their receptors in the modulation of immunity has never been studied in any rodent. The present study explores the role of Mel and its receptors (MT1 and MT2) in amelioration of immunocompromised state induced by a synthetic glucocorticoid, dexamethasone (Dex) in a tropical rodent Funambulus pennanti. Immune parameters viz. DTH response, Lymphocyte proliferation, cytokine (IL-2) and antibody production were assessed following pretreatment of Mel and Dex alone or in combination. Mel enhanced the IL-2 production, thymic and splenic lymphocyte proliferation thereby increasing T helper cell associated immune responses and anti-KLH-IgG production. MT1 and MT2 receptor expression was downregulated following Dex treatment while glucocorticoid receptors (GR) expression was downregulated in Mel treated groups suggesting that the immunomodulatory effects of glucocorticoids and Mel are mediated via their receptors. To gain further insights on the role of Mel receptors, we used nonselective melatonin receptor antagonist luzindole which resulted in reversal of most of the immunomodulatory actions of Mel. Therefore, it may be suggested that a physiological cross talk exist between Mel and GR which is of high adaptive significance in wild animals for balancing the immunity during ecologically stressful conditions.

Bidirectional communication between the pineal gland and the immune system.

The pineal gland is a vertebrate neuroendocrine organ converting environmental photoperiodic information into a biochemical message (melatonin) that subsequently regulates the activity of numerous target tissues after its release into the bloodstream. A phylogenetically conserved feature is increased melatonin synthesis during darkness, even though there are differences between mammals and birds in the regulation of rhythmic pinealocyte function. Membrane-bound melatonin receptors are found in many peripheral organs, including lymphoid glands and immune cells, from which melatonin receptor genes have been characterized and cloned. The expression of melatonin receptor genes within the immune system shows species and organ specificity. The pineal gland, via the rhythmical synthesis and release of melatonin, influences the development and function of the immune system, although the postreceptor signal transduction system is poorly understood. Circulating messages produced by activated immune cells are reciprocally perceived by the pineal gland and provide feedback for the regulation of pineal function. The pineal gland and the immune system are, therefore, reciprocally linked by bidirectional communication.