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Melatonin was initially extracted from the pineal gland and was thought to be produced exclusively by this organ. Subsequently it was shown that melatonin is also produced in other tissues including the gastrointestinal tract, retina and cells of the immune system. Melatonin is believed to be an important regulator of circadian and seasonal rhythms. Over the last thirty years, a great number of reports have documented a relationship between melatonin/pineal gland and the immune system in various species, including humans. In this review, current knowledge about the role of melatonin in the regulation of immune responses will be discussed.
Department of Human Developmental Biology, Jagiellonian University College of Medicine,
Kraków, Poland
Melatonin was initially extracted from the pineal gland and was thought to be
produced exclusively by this organ. Subsequently it was shown that melatonin is also
produced in other tissues including the gastrointestinal tract, retina and cells of the
immune system. Melatonin is believed to be an important regulator of circadian and
seasonal rhythms. Over the last thirty years, a great number of reports have
documented a relationship between melatonin/pineal gland and the immune system
in various species, including humans. In this review, current knowledge about the
role of melatonin in the regulation of immune responses will be discussed.
Key words: melatonin, immunoregulation, inflammation, innate immune response,
adaptive immune response.
Our bodies are constantly exposed to different microorganisms that are
present in the environment. However, contact with pathogenic microorganisms
rarely results in infection. This is because our bodies are protected by both innate
and adaptive immune mechanisms.
The innate immune system consists of many cells, such as macrophages,
dendritic cells, mast cells, neutrophils, eosinophils and natural killer (NK) cells.
These become activated during inflammation, which is virtually always a sign of
infection with pathogenic microbes (1). The main goal of these cells is to
eliminate the infection. It is worthy to underline that innate responses depend on
host recognition of highly conserved structures present on microorganisms called
"pathogen-associated molecular patterns" (PAMPs) (2). PAMPs are recognized by
"pathogen recognition receptors" (PRR) (2). The two major currently recognized
groups of PRRs in humans are toll-like receptors (TLRs) and nucleotide-binding
oligomerization domain (NOD)-containing proteins (3). Whereas TLRs are
associated with the plasma membrane or, in some case, with lysosomal and/or
endosomal vesicles, both NOD1 and NOD2 are present in the cytosol (4).
However, in certain types of infection, the innate immune system is not able
to deal with the infection and then an adaptive immune response is required. In
such infections, the innate immune system can instruct the adaptive immune
system regarding the nature of the pathogen through the expression of CD80 and
CD86 costimulatory molecules on dendritic cells and by producing cytokines to
direct the response.
There are two major classes of adaptive immune responses. The first, the so-
called "cellular response", is mediated by MHC II restricted, Th1 CD4
T cells
which drive delayed type hypersensitivity (DTH) responses, or MHC class I
restricted CD8
T cells which mediate direct cytotoxicity. The cellular response
is principally directed against intracellular pathogens (5). During the effector
phase of DTH, Th1 lymphocytes release proinflammatory cytokines like IFN-γ,
which induce local tissue cells to produce chemokines that recruit and activate an
infiltrate of bone marrow-derived leukocytes (6). CD8
T cytotoxic (Tc) cells kill
infected host cells via released perforin and granzymes and by triggering FasL
dependent apoptosis.
The second type of adaptive immune response is the humoral immune
response and is mediated by antibodies produced by B lymphocytes (1). In this
type of immune response, B cells receive support from Th2 T cells that produce
IL-4, IL-5, IL-6 and IL-13. The main function of the humoral response is to
destroy extracellular microorganisms and prevent the spread of infection. The
health of an organism is dependent on the ability of all of these branches of the
immune system to function together to protect from and control pathogenic
organisms as well as cancerous tissue. At the same time there must be
mechanisms to protect the organism from developing inappropriate immune
responses that are harmful to self (allergy, autoimmunity) as well as to control and
resolve inflammatory responses after clearance of the pathogen. This
demonstrates the importance of the balance of the immune response and its strict
control by regulatory mechanisms.
The immune response is negatively regulated by the action of T suppressor
(Ts) cells, which are also called T regulatory (Treg) cells. It is becoming
increasingly clear that there are multiple populations of T cells with regulatory
activity and that these can use different mechanisms, including direct cell-to-cell
contact and production of anti-inflammatory cytokines, to dampen the immune
response (7-9). Additionally, there is a body of evidence that the nervous and
endocrine systems can also interact with the immune system to modulate its
function (10). Indeed, it has been shown that many neurotransmitters,
neuroendocrine factors and hormones can dramatically alter immune function and
that, conversely, cytokines released by immune cells can affect the central
nervous system (11). It is also believed that environmental signals can regulate
many immune processes in different species including humans. It has been
demonstrated that light is one of the environmental signals that can modulate the
immune system. Although most of the light energy received by the retina is
relayed to the visual cortex for vision, an alternative pathway from the retina
relays a small part to the suprachiasmatic nucleus, which is part of the
hypothalamic region in the brain (12, 13). The suprachiasmatic nucleus is thought
to direct circadian rhythm and therefore controls many processes in the body such
as temperature, appetite, and mood (12). The pituitary and pineal glands are also
involved in light-induced neuroendocrine changes. The neuroendocrine
hormones that are sensitive to modifications in circadian rhythm are growth
hormone, thyroid hormones, thyroid-stimulating hormone, plasma cortisol and
melatonin (12, 14).
Over the last thirty years, a great number of reports have documented a
relationship between melatonin from the pineal gland and the immune system in
various species including humans (15, 16). Current knowledge about the role of
melatonin in the regulation of immune mechanisms will be discussed further below.
It is important to note that melatonin is produced not only by pineal gland, but
also in the retina, kidneys and digestive tract (17). This suggests that the immune
system might be affected by melatonin originating from different organs of the
body. Additionally it was found that human peripheral blood mononuclear cells
synthesize biologically relevant amounts of melatonin (18). This indicates a
potential intracrine and paracrine role of melatonin in immune regulation.
It is believed that melatonin influences cells of the immune system via
melatonin receptors. Both membrane and nuclear melatonin receptors have been
identified on leukocytes. Membrane receptors were found mostly on CD4
lymphocytes, but also on CD8 T and B cells (19-21). Through these receptors,
melatonin modulates the proliferative response of stimulated lymphocytes. On
the other hand, melatonin induces cytokine production by human peripheral
blood mononuclear cells via the nuclear melatonin receptor (22).
The immunoregulatory activity of melatonin was determined with the use of
following experimental models: surgical or functional pinealectomy, in vivo
treatment with melatonin or in vitro treatment of immune cells with melatonin.
Some studies demonstrated an immunoenhancing activity for melatonin. Daily
afternoon injections of melatonin induced an increase in thymus weight in the
gerbil (23) and spleen hypertrophy in the Syrian hamster (24). Treatment with
melatonin also increased the mitogenic response of mouse spleen cells to
concanavalin A and lipopolysaccharide (LPS) (25, 26). The mechanism by which
melatonin acts to enhance the immune response is not fully understood. It is
believed that, in part, it may act to increase phagocytosis and antigen presentation
(20). Indeed it was shown that treatment with melatonin enhanced antigen
presentation by splenic macrophages to T cells with a concurrent increase in
MHC class II expression and synthesis of the proinflammatory cytokines IL-1
and TNF-β (27). Additionally, melatonin was observed to induce IL-12
production to drive T cell differentiation towards the Th1 phenotype (28). The
activating effect of melatonin on the immune system is also mediated through the
regulation of gene expression of cytokines in the spleen, thymus, lymph nodes
and bone marrow. It was shown gene expression of M-CSF, TNF-α, TGF-β and
SCF was increased in peritoneal macrophages, while IL-1β, IFN-γ, M-CSF, TNF-
α and SCF was increased in spleen cells of mice treated with melatonin (29).
Other studies have shown that melatonin administration increases NK cell
activity in humans (30). Similar observations were made in mice where
treatment with melatonin increased antibody dependent cellular cytotoxicity
(ADCC) (31, 32). Aside from activation of immune cells by melatonin, this
hormone also enhances production of NK cells and monocytes in the bone
marrow of mice (33). Melatonin seems also to promote the survival of precursor
B cells in mouse bone marrow (34).
To summarize, melatonin is considered as a modulator of haemopoiesis and of
immune cell production and function. Melatonin has been demonstrated to
stimulate cytokine production, enhanced phagocytosis, increased NK cell activity
and skewing of the immune response toward a helper T cell type 1 profile. The
activating effect of melatonin on the immune system is presented in Fig. 1.
Melatonin has been shown to aggravate Th1 dependent inflammatory response
in animal models of multiple sclerosis (35) and rheumatoid arthritis (36).
Additionally, it was found in rats that melatonin is important in controlling cell
recruitment from the bone marrow and their subsequent migration to the lung. It
may suggest that melatonin is involved in allergic lung inflammation (37). This
observation is in line with human studies showing that elevated serum melatonin
is associated with the nocturnal worsening of asthma (38). Moreover, it is
suggested that melatonin may play a role in the etiology and treatment of several
dermatoses e.g. atopic eczema, psoriasis and malignant melanoma (39, 40).
Importantly, while many studies have implicated melatonin as a positive
regulator of immune responses, a number of other reports have suggested that
melatonin may act as an anti-inflammatory agent, inhibiting immune responses in
some cases. It is believed that the anti-inflammatory action of melatonin is at least
partly due to the induction of Th2 lymphocytes that produce IL-4, thereby
inhibiting the function of Th1 cells (41). Indeed, melatonin has been shown to be
protective in septic shock (42), an animal model of ulcerative colitis (43) and
experimental pancreatitis (44, 45).
Inflammation begins when cells within the infected tissue, whether they be
epithelial or stromal cells, tissue resident mast cells or dendritic cells, recognize
an inflammatory stimulus. These signals lead to the recruitment and activation of
effector cells of the immune system. As mentioned in Introduction, PRR (e.g.
TLR and NOD) play a crucial role in sensing microbial invaders by recognition
of PAMPS (46, 47). PRR ligation leads to the transcription of nuclear factor-
kappa B (NF-κB)-dependent genes, many of which encode for proinflammatory
cytokines and chemokines (48). Additionally, recognition of PAMPS by PRR
results in NF-κB-dependent expression of defensins that possess strong
bactericidal activity (49). NF-κB is also important for the synthesis of the
enzymes that generate prostaglandins and reactive oxygen species (e.g. COX and
iNOS), substances that are also involved in inflammation (48). Furthermore, the
expression of adhesion molecules on circulating leukocytes and endothelium
involved in leukocyte migration are also regulated by NF-κB (50, 51).
naive CD4
T cells
Th1 cells
Fig. 1. The activating effect of melatonin on the immune system.
Melatonin activates both innate (antigen presenting cells (APC), natural killer (NK) cells) and adaptive
immune responses (CD4
T lymphocytes).
Because NF-κB regulates a large number of genes involved in the immune
response and inflammation, this pathway is a likely target to silence chronic
inflammation that occurs in various diseases e.g. autoimmunity. Recently,
melatonin has been found to reduce NF-κB binding to DNA, probably by
preventing its translocation to the nucleus (52). This, in turn, reduced the
production of proinflammatory cytokines and chemokines. Additionally, because
melatonin has been shown to reduce adhesion of leukocytes to endothelium as
well as transendothelial migration, it may also suppress the expression of NF-κB-
regulated adhesion molecules (53). Finally, melatonin has been shown to reduce
recruitment of neutrophils to the site of inflammation (54, 55). The anti-
inflammatory effect of melatonin is presented in Fig. 2.
Septic shock caused by systemic bacterial infection is a form of
uncontrolled acute inflammatory response. This syndrome is characterized by
hypotension, inadequate perfusion, vascular damage and disseminated
intravascular coagulation leading to multiple organ failure and death (56). It is
known that many of the pathological symptoms of septic shock to Gram-
negative bacteria are attributable to (LPS) present in bacterial membranes.
Nitric oxide (NO) produced in response to LPS has been shown to be
responsible for LPS-induced hypotension and vascular hyporesponsiveness,
suggesting that excessive production of NO plays an important role in septic
adhesion molecules
Fig. 2. The anti-inflammatory effect
of melatonin.
Melatonin inhibits NF-κB binding to
DNA and prevents its translocation
to the nucleus. This, in turn, reduces
the production of proinflammatory
cytokines and chemokines.
Additionally, melatonin inhibits
expression of adhesion molecules
and suppresses synthesis of the
enzymes that generate
prostaglandins and reactive oxygen
species (e.g. COX and iNOS).
shock (57, 58). Importantly, melatonin has been shown to regulate NO
synthesis. Following on from these studies, Maestroni et al. investigated
whether melatonin could influence the pathology of septic shock (20). Indeed,
melatonin-treated mice were protected from LPS-induced shock and reduced
mortality correlated with reduced NO synthesis (59). It has been recently
reported that melatonin inhibits expression of iNOS in murine macrophages
via suppression of NF-κ B (60).
To summarize, melatonin is both a positive regulator of immune responses and
a negative regulator of inflammation.
Acknowledgements: This work was supported by grants from the Polish Committee of Scientific
research (KBN, Warsaw) No. 2 PO 5A 157 28, 2PO 5A 208 29 and the grant from the Polish
Committee of Scientific research (KBN, Warsaw) No. N N401 3553 33 to MS. The author is
indebted to Dr. S. Kerfoot for critical comments on the manuscript.
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Received: September 12, 2007
Accepted: November 14, 2007
Authors address: Marian Szczepanik, Department of Human Developmental Biology,
Jagiellonian University College of Medicine, ul. Kopernika 7, 31-034 Kraków, Poland; tel/fax: +48
12 422 99 49; e-mail:
... Early work indicated that the main function of melatonin was to regulate sleep (10,11). However, subsequent studies have reported that melatonin has a multitude of effects against tumors (12) and in the regulation of immunity (13). With regards to the treatment of breast cancer, melatonin has been shown to reduce the growth rate of breast tumor cells and inhibit the invasion and metastasis of tumor cells. ...
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... Melatonin is a hormone derived from tryptophan that is secreted primarily by the pineal gland at night (Hofstra and Weerd 2008). It has an important role in many physiological processes such as promoting sleep, regulating the circadian rhythm (Borjigin et al. 2012), and modulating the immune system (Szczepanik 2008) as well as reducing body weight and improving the lipid profile (Abou Fard et al. 2013). It acts as a strong antioxidant and antiinflammatory (Hacisevki and Baba 2018). ...
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The present study was carried out to investigate the ameliorative effects of melatonin against nicotine-induced heart and lung toxicity. For this purpose, 75 mature male Sprague Dawley (SD) rats weighing 150–170 g were randomly divided into five groups (15 rats each): control group (rats were I/P injected with 1% ethanol in saline), nicotine group (rats were I/P injected with 0.6 mg/kg body weight), and combined nicotine and melatonin groups (rats received nicotine as in the previous group and melatonin at a dose of 1, 5, or 10 mg/kg body weight, respectively); all treatments were continued for 21 days. Fasting blood samples were collected from each rat at the 11th day and one day after the end of the last injection (22nd day) for complete blood count (CBC) determination, while sera were collected for the determination of lipid profiles. Malondialdehyde (MDA) concentration, superoxide dismutase (SOD) activity, and reduced glutathione (GSH) as well as DNA fragmentation percentage were assessed in cardiac tissue. Heart and lung samples were collected for estimation of caspase-3 expression and histopathological examination. The results revealed that nicotine increased the number of RBCs, Hb concentration, total cholesterol, and low density lipoprotein (LDL) and decreased high density lipoprotein (HDL). In addition, it decreased SOD activity and GSH concentration with increased MDA concentration, and DNA fragmentation in the heart, as well as caspase-3 expression in both heart and lungs. It also induced histopathological changes in the heart and lung tissues. Melatonin could ameliorate the deleterious effect of nicotine on the previous parameters either partially or completely, where melatonin restored complete blood count, improved lipid profile, mended lipid peroxidation and antioxidant parameters in the cardiac tissue, rectified caspase-3 expression in the heart and lungs, ameliorated DNA fragmentation percentage in the heart, and protected both heart and lung tissue against the harmful effect of nicotine. It is concluded that melatonin has a protective effect on the heart and lungs against the harmful effect of nicotine.
... Melatonin (MT), the pineal gland's major secretory product under dark conditions in all mammals, including humans (Farías et al., 2012), is well known for its role in circadian rhythms and modulation of the immune system (Maestroni et al., 1986;Cagnacci et al., 1992;Szczepanik, 2007;Salehi et al., 2019). MT is already recognized for the treatment of sleep disorder (Jan et al., 1994;Buscemi et al., 2004;Xie et al., 2017). ...
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Melatonin (MT) has been recently considered an excellent candidate for the treatment of sleep disorders, neural injuries, and neurological diseases. To better investigate the actions of MT in various brain functions, real-time detection of MT concentrations in specific brain regions is much desired. Previously, we have demonstrated detection of exogenously administered MT in anesthetized mouse brain using square wave voltammetry (SWV). Here, for the first time, we show successful detection of exogenous MT in the brain using fast scan cyclic voltammetry (FSCV) on electrochemically pre-activated carbon fiber microelectrodes (CFEs). In vitro evaluation showed the highest sensitivity (28.1 nA/μM) and lowest detection limit (20.2 ± 4.8 nM) ever reported for MT detection at carbon surface. Additionally, an extensive CFE stability and fouling assessment demonstrated that a prolonged CFE pre-conditioning stabilizes the background, in vitro and in vivo, and provides consistent CFE sensitivity over time even in the presence of a high MT concentration. Finally, the stable in vivo background, with minimized CFE fouling, allows us to achieve a drift-free FSCV detection of exogenous administered MT in mouse brain over a period of 3 min, which is significantly longer than the duration limit (usually < 90 s) for traditional in vivo FSCV acquisition. The MT concentration and dynamics measured by FSCV are in good agreement with SWV, while microdialysis further validated the concentration range. These results demonstrated reliable MT detection using FSCV that has the potential to monitor MT in the brain over long periods of time.
... It is still undetermined whether the expression of COX-2 and ICAM-1 has a relation with NF-κB activation caused by exercise in the liver. However, it has been evidenced that NF-κB regulates the expression of adhesion molecules during leukocyte migration [32] and that the ICAM-1 promoter could be bind to the NF-κB binding site [33]. As expected, our research revealed that quercetin attenuated inflammatory stress and pathological malformation in mouse liver caused by continuous exhausting exercise, possibly by mainly suppressing nuclear translocation of NF-κB and the release of proinflammatory mediators. ...
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Background: Emerging evidence has supported that intensive exercise induces weakened performance and immune and metabolic disorders. We systematically evaluated the effects of quercetin against hepatic inflammatory damage caused by repeated intensive exercise and explored the potential mechanism. Methods: Male BALB/c mice were administered quercetin (100 mg/kg BW) for four weeks, and performed a treadmill running protocol of 28 m/min, 5° slope, 90 min/day concurrently for the last seven days. Results: Quercetin administration reduced the leakage of aspartic acid and alanine aminotransferase and improved ultrastructural abnormalities such as swelling, and degeneration caused by high-intensity running in mice. Quercetin significantly decreased the hepatic and plasmatic levels of inflammatory cytokines IL-1β, IL-6, TNF-α, inducible nitric oxide synthase, cyclooxygenase-2 and intercellular adhesion molecule-1-provoked by over-exercise. Furthermore, diminished activation and nuclear translocation of NF-κB were found after quercetin treatment through inhibiting IKKα and Iκbα phosphorylation of intensive running mice. Conclusion: Quercetin offers protection for mouse livers against intensive sports-induced inflammatory injury, and the suppression of the NF-κB signal transduction pathway may play a role in its anti-inflammatory effects. Our findings broaden our understanding of natural phytochemicals as a promising strategy to prevent excessive exercise damage.
One of the host risk factors involved in aging-related diseases is coupled with the reduction of endogenous melatonin (MLT) synthesis in the pineal gland. MLT is considered a well-known pleiotropic regulatory hormone to modulate a multitude of biological processes such as the regulation of circadian rhythm attended by potent anti-oxidant, anti-inflammatory, and anti-cancer properties. It has also been established that the microRNAs family, as non-coding mRNAs regulating post-transcriptional processes, also serve a crucial role to promote MLT-related advantageous effects in both experimental and clinical settings. Moreover, the anti-aging impact of MLT and miRNAs participation jointly are of particular interest, recently. In this review, we aimed to scrutinize recent advances concerning the therapeutic implications of MLT, particularly in the brain tissue in the face of aging. We also assessed the possible interplay between microRNAs and MLT, which could be considered a therapeutic strategy to slow down the aging process in the nervous system.
The current coronavirus disease 2019 (COVID‐19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), highlights major gaps in our knowledge on the prevention control and cross‐species transmission mechanisms of animal coronaviruses. Transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), and porcine delta‐coronavirus (PDCoV) are three common swine coronaviruses and have similar clinical features. In absence of effective treatments, they have led to significant economic losses in the swine industry worldwide. We reported that indoles exerted potent activity against swine coronaviruses, the molecules used included melatonin, indole, tryptamine and L‐tryptophan. Herein, we did further systematic studies with melatonin, a ubiquitous and versatile molecule, and found it inhibited TGEV, PEDV, and PDCoV infection in PK‐15, Vero, or LLC‐PK1 cells by reducing viral entry and replication respectively. Collectively, we provide the molecular basis for the development of new treatments based on the ability of indoles to control TGEV, PEDV, and PDCoV infection and spread.
Ethnopharmacological relevance The tea made with the fruits of Luffa operculata (L.) Cogn. (Cucurbitaceae; EBN) is popularly used as abortive. Aim of the study The present work aimed at accessing how the exposition of female Wistar rats to 1.0 mg/kg of EBN (experimental group, EG), or distilled water (control group, CG), by gavage, at gestational days (GD) 17 to 21 interfered with the reproductive performance, and with dams’ behavior after weaning. Materials and methods At post-natal day 2 (PND2), the number of male and female pups was evaluated, as well as their weight. After weaning (PND21), dams were euthanized, and their liver and kidneys were removed for histological and biochemical analyses, while the blood was used in the evaluation of cytokines IL-1α, IL-1β, IL-6 and TNF-α, corticosterone, adrenocorticotrophic hormone, melatonin, AST, ALT and creatinine levels. Results and Discussion: Dams that were treated with EBN showed an anxiety-like behavior, weight loss at the end of gestation and weight gain at weaning, accompanied with a significant decrease in pro-inflammatory cytokines and in the melatonin level. No significant histological or biochemical alterations have occurred in the liver or kidneys. The number of female pups was significantly higher in the EG. The male pups showed weight gain at PND60. Conclusion The presence of cucurbitacins is probably involved in the dysregulations that were found, due to their polycyclic steroid triterpene structure.
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Asthma is an inflammatory lung disease characterized by cell migration, bronchoconstriction and hyperresponsiveness, and can be induced, as an experimental model, by ovalbumin sensitization followed by a challenge. In addition to the well-known immunostimulatory effects of melatonin, research has identified some of its anti-inflammatory properties. In this study, we evaluated the influence of pinealectomy and melatonin administration on cell migration in an experimental model of allergic airway inflammation. We evaluated, in pinealectomized rats treated or not with melatonin, cell migration into the bronchoalveolar fluid, the number of cells and their proliferative activity in the bone marrow, and plasma corticosterone levels. Pinealectomy reduces, 24 hr after the challenge, the total cell number count in the lung and bone marrow cell proliferation, without changing the number of cells in the bone marrow or in the peripheral blood. This fact suggests that melatonin is important in the control of cell recruitment from the bone marrow and the migration of those cells to the lung. Melatonin administration to pinealectomized rats seems to restore the ability of cells to migrate from the bone marrow to the bronchoalveolar fluid. So, the development of specific inhibitors of melatonin would benefit patients with asthma.
There is now overwhelming evidence that cytokines, peptide hormones and neurotransmitters, as well as their receptors, are endogenous to the brain, endocrine and immune systems. Here, Edwin Blalock discusses how these shared ligands and receptors are used as a common chemical language for communication within and between the immune and neuroendocrine systems. Such communication suggests an immunoregulatory role for the brain and a sensory function for the immune system. A clearer understanding of this circuitry is dramatically altering our understanding of physiology and may profoundly affect the treatment of human disease.
Inhibition of synthesis of the pineal neurohormone melatonin (MEL) in mice, by administration of propranolol (PRO) in the evening, and daily injections of p-chlorophenylalanine (PCPA), resulted in a significant depression of the primary antibody response to sheep red blood cells (SRBC). Spleen cells from these mice showed a reduced reactivity against antigens in the autologous mixed lymphocyte reaction (AMLR). In contrast, alloreactivity remained normal. Reconstitution of the night-time peak of plasma MEL by evening injections to the mice completely reversed the suppression of the humoral response and the AMLR. MEL administration was able to antagonize the depression of antibody production induced by corticosterone in vivo. These results suggest that the pineal gland has important immunomodulatory functions through its cyclic, circadian release of MEL.
Paneth cells in mouse small intestinal crypts secrete granules rich in microbicidal peptides when exposed to bacteria or bacterial antigens. The dose-dependent secretion occurs within minutes and α-defensins, or cryptdins, account for 70% of the released bactericidal peptide activity. Gram-negative bacteria, Gram-positive bacteria, lipopolysaccharide, lipoteichoic acid, lipid A and muramyl dipeptide elicit cryptdin secretion. Live fungi and protozoa, however, do not stimulate degranulation. Thus intestinal Paneth cells contribute to innate immunity by sensing bacteria and bacterial antigens, and discharge microbicidal peptides at effective concentrations accordingly.
The pineal secretory product, melatonin, exerts a variety of effects on the immune system. Administration of melatonin stimulates cell-mediated immunity, particularly by inhibiting apoptosis among T lymphocytes in the thymus and inducing production of T-cell-derived cytokines. However, its possible effects on the humoral immune system are unclear. In the present study, we have examined whether melatonin may influence the in vivo development of B lymphocytes in mouse bone marrow, a process in which apoptosis is normally a prominent feature. Double immunofluorescence labeling and flow cytometry were used to quantitate phenotypically defined precursor B-cell and mature B-cell populations and their apoptotic rates in bone marrow of mice fed either melatonin-containing or control diet for 16 days from 9 wk of age. In short-term bone marrow cultures, the incidence of apoptosis among large pre-B cells, including cells expressing the Λ5 component of pre-B-cell receptor, was markedly reduced in melatonin-treated mice, associated with an increase in the absolute number of large pre-B cells in bone marrow. In contrast, apoptosis of earlier precursor B cells and mature B lymphocytes did not differ from control values. The results indicate that orally administered melatonin can substantially promote the survival of precursor B cells in mouse bone marrow. Melatonin treatment may thus boost the survival of newly formed B cells mediating humoral immunity.
Melatonin (N-acetyl-5-methoxytryptamine) was initially thought to be produced exclusively in the pineal gland. Subsequently its synthesis was demonstrated in other organs, for example, the retinas, and very high concentrations of melatonin are found at other sites, for example, bone marrow cells and bile. The origin of the high level of melatonin in these locations has not been definitively established, but it is likely not exclusively of pineal origin. Melatonin has been shown to possess anti-inflammatory effects, among a number of actions. Melatonin reduces tissue destruction during inflammatory reactions by a number of means. Thus melatonin, by virtue of its ability to directly scavenge toxic free radicals, reduces macromolecular damage in all organs. The free radicals and reactive oxygen and nitrogen species known to be scavenged by melatonin include the highly toxic hydroxyl radical (·OH), peroxynitrite anion (ONOO−), and hypochlorous acid (HOCl), among others. These agents all contribute to the inflammatory response and associated tissue destruction. Additionally, melatonin has other means to lower the damage resulting from inflammation. Thus, it prevents the translocation of nuclear factor-kappa B (NF-κB) to the nucleus and its binding to DNA, thereby reducing the upregulation of a variety of proinflammatory cytokines, for example, interleukins and tumor neurosis factor-alpha. Finally, there is indirect evidence that melatonin inhibits the production of adhesion molecules that promote the sticking of leukocytes to endothelial cells. By this means melatonin attenuates transendothelial cell migration and edema, which contribute to tissue damage.
Male and female gerbils were implanted s.c. with a pellet containing 2 mg melatonin/23 mg beeswax every 2 weeks for a total of 3 implants. A significant depression of ovarian and uterine weight was noted in female gerbils receiving melatonin implants. In the melatonin-treated male gerbils, growth of the accessory organs was significantly inhibited although testis size was not depressed.