Evidence for melatonin synthesis in the rat brain during development.

Melatonin production is not restricted to the pineal gland. Several extrapineal sources of this indole such as retina, Harderian gland, and immune system are well documented. Melatonin of pineal origin is not present in the rat at early stages of development.

NAP, a peptide derived from the activity-dependent neuroprotective protein, modulates macrophage function.

NAP is an eight-amino acid neuroprotective peptide NAPVSIPQ; it is the smallest active element derived from the recently cloned activity-dependent neuroprotective protein (ADNP). NAP readily enters the brain from the blood. It will be important to learn whether NAP, in addition to its neuroprotective activity, also might influence immune-mediated inflammation.

Protective role for plasmid DNA-mediated VIP gene transfer in non-obese diabetic mice.

Studies focused on the development of diabetes in NOD mice-a model for human type 1 diabetes-have revealed that an autoimmune inflammatory process is produced by the effect of Th1 cells and their secreted cytokines. DNA vaccination has been shown to be an effective method for modulating immunity in viral infections and experimental autoimmune diseases, including diabetes. VIP's immunomodulatory properties are partly mediated by skewing the pattern of cytokines from a proinflammatory response to an anti-inflammatory response.

A review of the multiple actions of melatonin on the immune system.

This review summarizes the numerous observations published in recent years which have shown that one of the most significant of melatonin's pleiotropic effects is the regulation of the immune system. The overview summarizes the immune effects of pinealectomy and the association between rhythmic melatonin production and adjustments in the immune system as markers of melatonin's immunomodulatory actions. The effects of both in vivo and in vitromelatonin administration on non-specific, humoral, and cellular immune responses as well as on cellular proliferation and immune mediator production are presented.

Beneficial pleiotropic actions of melatonin in an experimental model of septic shock in mice: regulation of pro-/anti-inflammatory cytokine network, protection against oxidative damage and anti-apoptotic effects.

Septic shock, the most severe problem of sepsis, is a lethal condition caused by the interaction of a pathogen-induced long chain of sequential intracellular events in immune cells, epithelium, endothelium, and the neuroendocrine system. The lethal effects of septic shock are associated with the production and release of numerous pro-inflammatory biochemical mediators including cytokines, nitric oxide and toxic oxygen and nitrogen radicals, together with development of massive apoptosis. As melatonin has remarkable properties as a cytokine modulator, antioxidant and anti-apoptotic agent, the present study was designed to evaluate the possible protective effect of melatonin against LPS-induced septic shock in Swiss mice.

Melatonin synthesis and melatonin-membrane receptor (MT1) expression during rat thymus development: role of the pineal gland.

To gain insight into the relationship between thymus and pineal gland during rat development, the melatonin content as well as the activity and expression of the two key enzymes for melatonin biosynthesis, i.e. N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT), were studied in the thymus at fetal and postnatal stages.

Dual effect of melatonin as proinflammatory and antioxidant in collagen-induced arthritis in rats.

The aim of this study was to determine the effects of melatonin on proinflammatory status of rats with collagen-induced arthritis (CIA). CIA was induced in male Wistar rats with an emulsion of type II collagen in Freund's Incomplete Adjuvant (C-II/FIA). For 14 days, control and pinealectomized rats received a subcutaneous injection of 100 microL melatonin (30 microg) or vehicle (saline on 1% ethanol).

Human lymphocyte-synthesized melatonin is involved in the regulation of the interleukin-2/interleukin-2 receptor system.

Since melatonin was first isolated in 1958 up to the last few years, this substance was considered a hormone exclusive to the pineal gland. Although melatonin has lately been identified in a large number of extrapineal sites, its potential biological actions have not yet been studied. This paper shows that human lymphocyte-synthesized melatonin plays a crucial role modulating IL-2/IL-2 receptor system because when blocking melatonin biosynthesis by the tryptophan hydroxylase inhibitor, parachlorophenylalanine, both IL-2 and IL-2 receptor levels fell, restoring them by adding exogenous melatonin.

Expression of membrane and nuclear melatonin receptors in mouse peripheral organs.

Previous studies have shown that melatonin acts through specific receptors, including MT(1) and MT(2) membrane receptors as well as a nuclear receptor belonging to the orphan nuclear receptor family. Therefore, the goal of this study was to determine whether melatonin receptors mRNA is expressed in mouse peripheral tissues. To study the different receptors subtype expression, we have used a reverse-transcription polymerase chain reaction (RT-PCR) procedure followed by Southern hybridization with specific digoxigenin-labeled probes.

Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and/or paracrine substance.

It has been historically assumed that the pineal gland is the major source of melatonin (N-acetyl-5-methoxytryptamine) in vertebrates. Melatonin plays a central role in fine-tuning circadian rhythms in vertebrate physiology. In addition, melatonin shows a remarkable functional versatility exhibiting antioxidant, oncostatic, antiaging, and immunomodulatory properties.

Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system.

The neurohormone melatonin plays a fundamental role in neuroimmunomodulation of several mammalian species, including mice. This effect is supported by the existence of specific melatonin-binding sites in murine immunocompetent organs. Moreover, using melatonin receptor analogues, several effects of the neurohormone on mice physiology through its membrane and nuclear receptors have been described.

Melatonin inhibits telomerase activity in the MCF-7 tumor cell line both in vivo and in vitro.

In this study for the first time the relationship between melatonin and telomerase activity was investigated. Melatonin exhibits oncostatic properties, but the actual mechanism of action by which the indole reduces tumor cell activity is not clear. Telomerase is an enzyme responsible of telomere elongation and is activated in most human cancers.

Melatonin counteracts the inhibitory effect of PGE2 on IL-2 production in human lymphocytes via its mt1 membrane receptor.

It is well known that melatonin plays a fundamental role in human neuro-immunomodulation. Thus, melatonin regulates the production of a large number of cytokines, including interleukin-2 (IL-2) in the human system. Both membrane and nuclear receptors for melatonin are present in lymphoid cells.

Melatonin prevents the formation of pyrrolized proteins in human plasma induced by hydrogen peroxide.

This report presents a model of oxidative stress, which includes formation of pyrrolized proteins in human plasma. Pyrroles were determined using Ehrlich's reagent under acid conditions. Adduct formation in plasma proteins was induced by hydrogen peroxide (H(2)O(2)) in a dose-dependent manner.

Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit LPS-stimulated MIP-1alpha production and mRNA expression.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are neuropeptides with immunomodulatory properties, including the regulation of several proinflammatory mediators. Such mediators, for example chemokines, influence trafficking of inflammatory cells and contribute to shaping the immune response. In the present work, we studied the effect of VIP and PACAP on the CC chemokine macrophage inflammatory protein-1 alpha (MIP-1alpha) production in LPS-stimulated RAW 264.

Melatonin-immune system relationships.

In this paper we review the historical milestones that first highlighted the existence of a relationship between melatonin and the immune system and we summarize data from experiments which correlate the rhythmic production of melatonin with the rhythmic activity of the immune system. The effects of pinealectomy and in vivo administration of melatonin on a variety of immune parameters, including specific and non-specific immunity are considered and we also present contradictory data concerning the effect of melatonin in cultured immunocompetent cells and a possible scheme of how melatonin regulates the production of a number of cytokines. Finally, the mechanism of action of melatonin in the immune system is discussed.

Correlation between nuclear melatonin receptor expression and enhanced cytokine production in human lymphocytic and monocytic cell lines.

The report shows that melatonin enhances IL-2 and IL-6 production by two human lymphocytic (Jurkat) and monocytic (U937) cell lines via a nuclear receptor-mediated mechanism. Jurkat cells express nuclear (RZRalpha, RORalpha1 and RORalpha2) and membrane (mt1) melatonin receptors, and melatonin binds to Jurkat nuclei and membranes with the same affinity described for human peripheral blood mononuclear cells (PBMCs). Melatonin enhances IL-2 production by Jurkat cells activated by either phytohemagglutinin (PHA) or phorbol myristate acetate (PMA).

Nuclear receptors are involved in the enhanced IL-6 production by melatonin in U937 cells.

This report shows that melatonin enhances IL-6 production by U937 cells via a nuclear receptor-mediated mechanism. Resting U937 cells only express membrane (mt1) melatonin receptors. In these cells, melatonin did not modify basal production of IL-6 or when activated by PMA plus lipopolysaccharide, a treatment that downregulates the expression of mt1 receptor.

Serum cholesterol and lipid peroxidation are decreased by melatonin in diet-induced hypercholesterolemic rats.

The purpose of this study was to investigate the effect of melatonin, at pharmacological doses, on serum lipids of rats fed with a hypercholesterolemic diet. Therefore, different groups of animals were fed with either the regular Sanders Chow diet or a diet enriched in cholesterol. Moreover, animals were treated with or without melatonin in the drinking water for 3 months.

Functional and molecular characterization of VIP receptor--effector system in rat developing immunocompetent cells: G protein involvement.

Changes in the functional characteristics for vasoactive intestinal peptide (VIP) receptor-effector system were evaluated in rat developing immunocompetent cells (from 1-week-old animals up to 12-week-old animals). These characteristics include [125I]VIP binding studies, cell cyclic AMP (cAMP) generation, analysis of [125I]VIP-receptor complexes by cross-linking experiments, as well as developed-associated G proteins assayed by cholera and pertussis toxin-catalyzed ADP-ribosylation and Western blot. The Scatchard analysis of binding data was consistent with the existence of two classes of VIP binding sites with K(d) values unaltered and B(max) increased during postnatal development.

Melatonin activates Th1 lymphocytes by increasing IL-12 production.

Melatonin could act on immune system by regulating cytokine production of immunocompetent cells. The hormone enhances IL-2, IFN-gamma and IL-6 production by cultured human mononuclear cells. As enhancement of IL-6 production is related to monocyte activation by melatonin, the hormone acts on human lymphoid cells causing a Th1-type response.

Physiological levels of melatonin contribute to the antioxidant capacity of human serum.

This work evaluates whether physiological concentrations of the pineal secretory product melatonin contribute to the total antioxidant status (TAS) of human serum. Day and nighttime serum samples were collected from healthy volunteers ranging from 2 to 89 years of age and used to measure melatonin and TAS. Results showed that both melatonin and TAS in human serum exhibited 24 hr variations with nocturnal peak values at 01:00 hr.

The pineal secretory product melatonin reduces hydrogen peroxide-induced DNA damage in U-937 cells.

Melatonin, the chief secretory product of the pineal gland, is a potent and efficient endogenous radical scavenger. Thus, melatonin was shown to protect different biomolecules, such as DNA, membrane lipids, and cytosolic proteins, from oxidative damage induced by oxygen-derived free radicals. In order to study the protective role of melatonin in hydrogen peroxide (H2O2)-induced DNA damage, U-937 cells were treated with different concentrations of H2O2, either in the presence or absence of melatonin, and DNA damage was assessed using the cytokinesis-block micronucleus technique.

Characterization of membrane melatonin receptor in mouse peritoneal macrophages: inhibition of adenylyl cyclase by a pertussis toxin-sensitive G protein.

Melatonin binding sites were characterized in mouse peritoneal macrophages. Binding of 2-[125I]melatonin by macrophages fulfills all criteria for binding to a receptor site. Thus, binding was dependent on time, temperature and cell concentration, stable, reversible, saturable and specific.