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Abstract

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.
M. SZCZEPANIK
MELATONIN AND ITS INFLUENCE ON IMMUNE SYSTEM
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.
INTRODUCTION
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
JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2007, 58, Suppl 6, 115124
www.jpp.krakow.pl
"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.
DIFFERENT MECHANISMS OF IMMUNOREGULATION
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
116
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.
THE INFLUENCE OF MELATONIN ON THE IMMUNE SYSTEM
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
+
T
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
117
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
118
protective in septic shock (42), an animal model of ulcerative colitis (43) and
experimental pancreatitis (44, 45).
MELATONIN AND INFLAMMATION
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).
119
MELATONIN
APC
naive CD4
+
T cells
NK
Th1 cells
IL-12
+
IL-1
TNF-ȕ
phagocytosis
Ĺ MHC II
+
+
+
INF-Ȗ
+
+
+
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
120
CELL
MEMBRANE
TLRENDOSOME
TLR
NOD
NF-țB
IțB
NUCLEUS
cytokines
chemokines
defensins
COX
iNOS
adhesion molecules
MELATONIN
+
+
+
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: mmszczep@cyf-kr.edu.pl
124
... For example, the presence of these receptors in bone marrow stem cells (BMSC) (29,30) indicates an important role in the maintenance and recovery of the haematopoietic system. Its central role in influencing the immune response has gained importance in a variety of research areas for the treatment of several diseases (31,32). Radiation-induced injuries are due to an increase in free radical burden, inflammation, and pathogenesis in sensitive organs, if not intervened, can lead to syndromes. ...
... Due to this importance, a large number of radiomitigators are under investigation in rodents (Table I). Because melatonin has multiple properties, and its role as an "immunological buffer", a large number of studies have already been undertaken for different disease models in small animals (31,32). The range of indications includes inflammation, immune dysfunction, infections, cancer, and metabolic disorders. ...
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... Melatonin is a direct actor in immune system response through the stimulation of T-Lymphocytes, interleukin-2 and -6, and natural killer cells (Cherry, 2002;Peña et al., 2007;Szczepanik, 2007). The role of melatonin levels on immune system outcomes is thought to be modulated by cytokines. ...
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