Melatonin mediates seasonal adjustments in immune function.

In addition to seasonal changes in reproductive function, seasonal changes in immune function are mediated by the pineal hormone, melatonin. Melatonin affects immune function both indirectly, acting through other hormones, and directly by acting on components of the immune system. Melatonin also affects tumorigenesis and tumor development. We hypothesize that many of the indirect effects of melatonin on immune function are mediated through glucocorticoids, and appear to be part of an integrated series of adaptations to manage energy. Direct effects of melatonin on immune function appear to be mediated by melatonin receptors on lymphatic tissue or on immune cells in circulation. Winter is energetically demanding and stressful; thermoregulatory demands typically increase when food availability decreases. Individuals would enjoy a survival advantage if seasonally recurring stressors could be anticipated and countered by bolstering immune function. To summarize, melatonin may be part of an integrative system to coordinate reproductive, immunologic and other physiological processes to cope successfully with energetic stressors during winter.     

Immunoregulatory role of melatonin in cancer

Melatonin is a ubiquitous indole amine that plays a fundamental role in the regulation of the biological rhythm. Disrupted circadian rhythm alters the expression of clock genes and deregulates oncogenes, which finally promote tumor development and progression. An evidence supporting this notion is the higher risk of developing malignancies among night shift workers. Circadian secretion of the pineal hormone also synchronizes the immune system via a reciprocal association that exists between the immune system and melatonin. Immune cells are capable of melatonin biosynthesis in addition to the expression of its receptors. Melatonin induces big changes in different immune cell proportions, enhances their viability and improves immune cell metabolism in the tumor microenvironment. These effects might be directly mediated by melatonin receptors or indirectly through alterations in hormonal and cytokine release. Moreover, melatonin induces apoptosis in tumor cells via the intrinsic and extrinsic pathways of apoptosis, while it protectsthe immune cells. In general, melatonin has a profound impact on immune cell trafficking, cytokine production and apoptosis induction in malignant cells. On such a basis, using melatonin and resynchronization of sleep cycle may have potential implications in immune function enhancement against malignancies, which will be the focus of the present paper.     

Minireview: Versatile Melatonin: A Pervasive Molecule Serves Various Functions in Signaling and Protection

Melatonin, which is able to enter all tissues and all compartments of the cell, acts in a highly pleiotropic fashion. Some melatonin effects are mediated by membrane receptors, others are receptor independent. Melatonin is produced in the pineal gland and various extrapineal organs of vertebrates, but is also found in invertebrates, angiosperms, and unicells. In mammals, melatonin elicits various secondary humoral responses, e.g., in the immune system via interleukin-4 and other cytokines and in the brain by modulation of NO formation. Melatonin is also a powerful radical scavenger, terminating free radical reaction chains initiated by photooxidants, hydroxyl or peroxyl radicals. The protective potency of this indoleamine is demonstrated by various experiments.     

Minireview: Versatile Melatonin: A Pervasive Molecule Serves Various Functions in Signaling and Protection

Melatonin, which is able to enter all tissues and all compartments of the cell, acts in a highly pleiotropic fashion. Some melatonin effects are mediated by membrane receptors, others are receptor independent. Melatonin is produced in the pineal gland and various extrapineal organs of vertebrates, but is also found in invertebrates, angiosperms, and unicells. In mammals, melatonin elicits various secondary humoral responses, e.g., in the immune system via interleukin-4 and other cytokines and in the brain by modulation of NO formation. Melatonin is also a powerful radical scavenger, terminating free radical reaction chains initiated by photooxidants, hydroxyl or peroxyl radicals. The protective potency of this indoleamine is demonstrated by various experiments.     

Toll-like receptors: a family of pattern-recognition receptors in mammals

The innate immune system uses a variety of germline-encoded pattern-recognition receptors that recognize conserved microbial structures or pathogen-associated molecular patterns, such as those that occur in the bacterial cell-wall components peptidoglycan and lipopolysaccharide. Recent studies have highlighted the importance of Toll-like receptors (TLRs) as a family of pattern-recognition receptors in mammals that can discriminate between chemically diverse classes of microbial products. First identified on the basis of sequence similarity with the Drosophila protein Toll, TLRs are members of an ancient superfamily of proteins, which includes related proteins in invertebrates and plants. TLRs activate innate immune defense reactions, such as the release of inflammatory cytokines, but increasing evidence supports an additional critical role for TLRs in orchestrating the development of adaptive immune responses. The sequence similarity between the intracellular domains of the TLRs and the mammalian interleukin-1 and interleukin-18 cytokine receptors reflects the use of a common intracellular signal-transduction cascade triggered by these receptor classes. But more recent findings have demonstrated that there are in fact TLR-specific signaling pathways and cellular responses. Thus, TLRs function as sentinels of the mammalian immune system that can discriminate between diverse pathogen-associated molecular patterns and then elicit pathogen-specific cellular immune responses.     

Melatonin and pancreatic cancer: Current knowledge and future perspectives

Pancreatic cancer has a high mortality rate due to the absence of early symptoms and subsequent late diagnosis; additionally, pancreatic cancer has a high resistance to radio- and chemotherapy. Multiple inflammatory pathways are involved in the pathophysiology of pancreatic cancer. Melatonin an indoleamine produced in the pineal gland mediated and receptor-independent action is the pancreas and other where has both receptors. Melatonin is a potent antioxidant and tissue protector against inflammation and oxidative stress. In vivo and in vitro studies have shown that melatonin supplementation is an appropriate therapeutic approach for pancreatic cancer. Melatonin may be an effective apoptosis inducer in cancer cells through regulation of a large number of molecular pathways including oxidative stress, heat shock proteins, and vascular endothelial growth factor. Limited clinical studies, however, have evaluated the role of melatonin in pancreatic cancer. This review summarizes what is known regarding the effects of melatonin on pancreatic cancer and the mechanisms involved.     

Toll样受体信号通路的负调控

综述了Toll样受体(Toll-like receptors,TLRs)介导炎症反应信号通路的负调控机理．TLRs可以被病原体激活并迅速启动炎症反应,对先天性和获得性免疫反应起着重要调节作用．TLRs介导的免疫反应必须受到严格的调控,持续激活状态可长时间高表达炎症因子,导致机体产生慢性炎症、自身免疫紊乱和其他TLRs相关疾病．正常生理状态下,机体存在着多种TLRs的负调控机制,以维持免疫反应的平衡．该领域的研究近年来取得了重要进展,为许多免疫相关疾病的治疗提供了线索．     

Toll-like receptors signaling network in pre-eclampsia: An updated review

Toll-like receptors (TLRs) are innate immune cells receptors. They are expressed on leukocytes, epithelial cells, and more particularly on placental immune cells and chorion trophoblast. Upregulation of innate immune response occurs during normal pregnancy, but its excessive activity is involved in the pathology of pregnancy complications including pregnancy-induced hypertension and pre-eclampsia (PE). The recent studies about the overmuch inflammatory responses and aberrant placentation are associated with increased expression of TLRs in PE patients. This review has tried to focus on the relationship between some activities of TLRs and the risk of preeclampsia development.     

Toll-like receptors are key participants in innate immune responses

During an infection, one of the principal challenges for the host is to detect the pathogen and activate a rapid defensive response. The Toll-like family of receptors (TLRs), among other pattern recognition receptors (PRR), performs this detection process in vertebrate and invertebrate organisms. These type I transmembrane receptors identify microbial conserved structures or pathogen-associated molecular patterns (PAMPs). Recognition of microbial components by TLRs initiates signaling transduction pathways that induce gene expression. These gene products regulate innate immune responses and further develop an antigen-specific acquired immunity. TLR signaling pathways are regulated by intracellular adaptor molecules, such as MyD88, TIRAP/Mal, between others that provide specificity of individual TLR- mediated signaling pathways. TLR-mediated activation of innate immunity is involved not only in host defense against pathogens but also in immune disorders. The involvement of TLR-mediated pathways in auto-immune and inflammatory diseases is described in this review article.     

Dexamethasone modulates melatonin MT2 receptor expression in splenic tissue and humoral immune response in mice

Melatonin modulates immune function through its membrane-bound MT1 and MT2 receptors in mammalian system. Adrenal glucocorticoid, an important metabolic hormone is known as a immuno-compromising agent. In the present study, we investigated the effect of dexamethasone on melatonin receptor proteins in spleen tissue and anti-klh-IgG response in Swiss albino mice. Melatonin treatment increased the MT1 and MT2 receptor proteins and anti-klh-IgG than control mice. Dexamethasone treatment increased MT2 receptor protein and anti-klh-IgG than melatonin-treated group. Dexamethasone treatment to melatonin-treated mice showed additive effects and maximally increased the anti-klh-IgG than other experimental groups. A decrease in glucocorticoid receptor (GR) protein was noted in melatonin treated as well as dexamethasone-treated mice. Dexamethasone significantly increased MT2 melatonin receptor protein in spleen and anti-klh-IgG and additively increased anti-klh-IgG when supplemented along with melatonin. Therefore, the present study may suggest that dexamethasone increased humoral immune response permissively by enhancing MT2 receptor expression in splenic tissue of mice.     

Intracellular NOD-like receptors in innate immunity, infection and disease

The innate immune system comprises several classes of pattern-recognition receptors, including Toll-like receptors (TLRs) and nucleotide binding and oligomerization domain-like receptors (NLRs). TLRs recognize microbes on the cell surface and in endosomes, whereas NLRs sense microbial molecules in the cytosol. In this review, we focus on the role of NLRs in host defence against bacterial pathogens. Nod1 and Nod2 sense the cytosolic presence of molecules containing meso-diaminopimelic acid and muramyl dipeptide respectively, and drive the activation of mitogen-activated protein kinase and NF-κB. In contrast, Ipaf, Nalp1b and Cryopyrin/Nalp3 promote the assembly of inflammasomes that are required for the activation of caspase-1. Mutation in several NLR members, including NOD2 and Cryopyrin, is associated with the development of inflammatory disorders. Further understanding of NLRs should provide new insights into the mechanisms of host defence and the pathogenesis of inflammatory diseases.     

Toll-like receptors and innate immunity

Toll-like receptors (TLRs) are evolutionarily conserved innate receptors expressed in various immune and non-immune cells of the mammalian host. TLRs play a crucial role in defending against pathogenic microbial infection through the induction of inflammatory cytokines and type I interferons. Furthermore, TLRs also play roles in shaping pathogen-specific humoral and cellular adaptive immune responses. In this review, we describe the recent advances in pathogen recognition by TLRs and TLR signaling.     

Melatonin and sleep

Sleep-wake cycle is the predominant example of circadian rhythms. Melatonin is commonly used to treat insomnia and in additional neurodevelopmental disorders in which sleep disturbance is frequent. In mammals, melatonin receptors are present in the membrane and cell nucleus of many tissues and systems where it exhibits various actions, including the regulation of circadian rhythms. The rhythmic pattern of melatonin secretion is imperative since it endows with vital information to the organism concerning time, which permits for alterations of a number of physiological functions consistent with daily and seasonal variations. Melatonin as well has sleep promoting effects demonstrated in changes in brain activation patterns and tiredness generation. The SCN’s (suprachiasmatic nuclei) function and melatonin production capability turns down with age consequently depriving the brain from an important time cue and sleep regulator.     

Steroid hormone receptors in the thymus: a site of immunomodulatory action of melatonin.

1. Melatonin and glucocorticoids are known to affect the immune response in an opposite mode. The probability for an interaction between these hormones in the thymus gland has been investigated in rats following chronic administration of exogenous melatonin and long-term exposure to variable levels of circulating glucocorticoids. 2. Daily melatonin administration was shown to affect the properties of corticosterone and progestin receptors in the thymus in the presence of normal and increased systemic corticosterone concentrations, but not in adrenalectomized animals. 3. In intact rats melatonin caused a marked increase in the affinity and a decrease in the density of thymic receptors for adrenal steroids. Following corticosterone overdosage, simultaneously with melatonin treatment, a decrease in receptor affinity and a relative increase in the number of binding sites was observed. 4. The results suggest that steroid hormone receptors in the thymus might be considered as a target site for the interaction between melatonin and adrenal steroids in the modulation of the immune response.     

The negative regulation of Toll-like receptor and associated pathways

Toll-like receptors (TLRs) are essential mediators of both innate and adaptive immunity by recognizing and eliciting responses upon invasion of pathogens. The response of TLRs must be stringently regulated as exaggerated expression of signalling components as well as pro-inflammatory cytokines can have devastating effects on the host, resulting in chronic inflammatory diseases, autoimmune disorders and aid in the pathogenesis of TLR-associated human diseases. Therefore, it is essential that negative regulators act at multiple levels within TLR signalling cascades, as well as through eliciting negative-feedback mechanisms in order to synchronize the positive activation and negative regulation of signal transduction to avert potentially harmful immunological consequences. This review explores the various mechanisms employed by negative regulators to ensure the appropriate modulation of both immune and inflammatory responses.     

Melatonin: A hormone that modulates pain

AimsMelatonin is a hormone synthesized principally in the pineal gland that has been classically associated with endocrine actions. However, several lines of evidence suggest that melatonin plays a role in pain modulation. This paper reviews the available evidence on melatonin's analgesic effects in animals and human beings.Main methodsA medline search was performed using the terms “melatonin”, “inflammatory pain”, “neuropathic pain”, “functional pain”, “rats”, “mice”, “human”, “receptors”, “opioid” and “free radicals” in combinations.Key findingsThe antinociceptive effect of melatonin has been evaluated in diverse pain models, and several findings show that melatonin receptors modulate pain mechanisms as activation induces an antinociceptive effect at spinal and supraspinal levels under conditions of acute and inflammatory pain. More recently, melatonin induced-antinociception has been extended to neuropathic pain states. This effect agrees with the localization of melatonin receptors in thalamus, hypothalamus, dorsal horn of the spinal cord, spinal trigeminal tract, and trigeminal nucleus. The effects of melatonin result from activation of MT₁ and MT₂ melatonin receptors, which leads to reduced cyclic AMP formation and reduced nociception. In addition, melatonin is able to activate opioid receptors indirectly, to open several K⁺ channels and to inhibit expression of 5-lipoxygenase and cyclooxygenase 2. This hormone also inhibits the production of pro-inflammatory cytokines, modulates GABA_A receptor function and acts as a free radical scavenger.SignificanceMelatonin receptors constitute attractive targets for developing analgesic drugs, and their activation may prove to be a useful strategy to generate analgesics with a novel mechanism of action.     

Monocyte and macrophage heterogeneity and Toll-like receptors in the lung

Mononuclear phagocytes are crucial components of the innate host defense system. Cells such as macrophages and monocytes phagocytose and process pathogens, produce inflammatory mediators, and link the innate and the adaptive immune systems. The role of innate immune receptors such as Toll-like receptors (TLRs) in the recognition of pathogens is critical for mounting a precise and targeted immune response. This review focuses attention on the development of monocytes and macrophages, various populations of macrophages, and the expression and function of TLRs on macrophages.     

Melatonin,a calpain inhibitor in the central nervous system: Current status and future perspectives

Dysregulation of neuronal Ca²⁺ and oxidative stress plays an important role in the activation of cysteine proteases including calpains and caspases that contribute to neuronal death. In neurodegenerative diseases, traumatic brain injury, stroke, and neuropathic pain calpain activities are markedly increased. Melatonin is a beneficial supplement in the treatment of central nervous system (CNS) disorders. Melatonin is a potent antioxidant and works as a free-radical scavenger to regulate a large number of molecular pathways, including oxidative stress, inflammation, apoptosis, and cell death under different pathological conditions. However, limited studies have evaluated the inhibitory effect of melatonin on calpains. This review summarizes the current knowledge related to the effects of melatonin on calpains in some of the common CNS disorders.     

Toll-like receptors are potential therapeutic targets in rheumatoid arthritis

Toll-like receptors (TLRs) are found on the membranes of pattern recognition receptors and not only play important roles in activating immune responses but are also involved in the pathogenesis of inflammatory disease, injury and cancer. Furthermore, TLRs are also able to recognize endogenous alarmins released by damaged tissue and necrosis and/or apoptotic cells and are present in numerous autoimmune diseases. Therefore, the release of endogenous TLR ligands plays an important role in initiating and driving inflammatory diseases. Increasing data suggest a role for TLR signaling in rheumatoid arthritis, which is an autoimmune disease. Although their involvement is not comprehensively understood, the TLRs signaling transducers may provide potential therapeutic targets.