RESEARCH - The melatonin-cytokine connection in RA

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ls of the Rheumatic Diseases 2005;64:1109-1111; doi:10.1136/ard.2005.038588

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LEADER

Rheumatoid arthritis

The melatonin-cytokine connection in rheumatoid arthritis

M Cutolo 1, G J M Maestroni 2

1 Research Laboratory and Division of Rheumatology, Department of

Internal Medicine, University of Genova, Viale Benedetto XV,6, 16132

Genova, Italy

2 Centre for Experimental Pathology, Cantonal Institute of Pathology,

Via In Selva 24, PO Box, 6601 Locarno, Switzerland

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Melatonin up regulates cytokine production and immune function

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A substance from pineal gland extracts, which lightens the skin

melanocytes of amphibians and fishes, was isolated in 1958 and called

melatonin (MLT, N-acetyl-5-methoxytryptamine).1 In both diurnal and

nocturnal species, the absence of light at night stimulates MLT

biosynthesis. Electrical signals originating from the retina reach the

suprachiasmatic nuclei which, in turn, send inputs via the

paraventricular nuclei to the spinal cord and then to the superior

cervical ganglia. The fibres terminate at the pinealocytes.2 Absence

of light results in increased norepinephrine release and activation of

1 and ß-adrenergic receptors on the pinealocytes. This triggers a

series of intracellular responses, resulting in activation of the

enzymes N-acetyltransferase (EC 2.3.1.87) and hydroxyindole-O-methyl

transferase (EC 2.1.1.4), which convert serotonin into MLT.2 The

circadian nocturnal release of MLT has a profound influence on the

internal environment of the organism, with diverse physiological

effects. The main function of MLT seems to be that of synchronising

the organism in the photoperiod and it may have a role in

reproduction, metabolism, seasonality, thermoregulation, and immunity.

MELATONIN AND THE HUMAN IMMUNE SYSTEM

Animal studies have shown that binding of MLT to specific receptors in

antigen activated T helper (Th) cells results in an up regulation of

cytokine production and immune function.3 In general, the

immunoenhancing action of MLT seems restricted to T dependent antigens

and to be most pronounced in immunodepressed situations. For example,

MLT may completely counteract thymus involution and the immunological

depression induced by stress or glucocorticoid treatment,4 or restore

depressed immunological functions after soft tissue trauma and

haemorrhagic shock.5 MLT may also rescue haematopoiesis in mice

treated with cancer chemotherapeutic compounds.6 This effect

apparently involves the endogenous release of granulocyte/macrophage

colony stimulating factor and MLT-induced opioid cytokines.3,6,7

The immunoenhancing action of MLT has been confirmed and extended in a

variety of animal species and in humans and in birds.8,9,10,11,12 In

human peripheral blood mononuclear cells, at physiological

concentrations MLT has been reported to stimulate the production of

interleukin 1 (IL1), IL2, interferon (IFN), IL6, and IL12 but not

IL4.13–15 Physiologically, the nocturnal MLT peak has been associated

with a high IFN/IL10 ratio—that is, the MLT rhythm positively

correlates with the rhythmicity of the Th1/Th2 cell ratio.16 In

patients with ischaemic stroke an impaired nocturnal MLT excretion has

been associated with impaired cell mediated immunity and changes of

lymphocyte subsets.17 Most interestingly, reduction of MLT secretion

has been reported to parallel disease progression and to correlate

with serum IL12 levels in HIV-1 infected patients.18 These human

studies confirmed that MLT possesses important immunoenhancing

properties and suggest that MLT may favour a Th1 cell response.

" MLT possesses important immunoenhancing properties "

Most recently, the connection between IL2 and MLT in human lymphocytes

has been strengthened by the observation that MLT may be synthesised

and released in large quantity by human lymphocytes.19,20 The

lymphocyte MLT production seems to be strictly linked to the release

of IL2 as inhibition of MLT synthesis resulted in a decrease of IL2

production and addition of exogenous MLT resulted in an increase of

IL2 production. These findings indicate that in addition to pineal

gland, human lymphoid cells are an important physiological source of

melatonin and that this melatonin might play a part in the regulation

of the human immune system, possibly by acting as an intracrine,

autocrine, and/or paracrine substance.13,14,19,20 The MLT/IL2

connection seems particularly relevant because IL2 has a central role

in immune homoeostasis. Recent studies indicate that a failure in the

production of CD4+CD25+ regulatory T cells is the underlying cause of

autoimmunity in the absence of IL2.21 Yet, IL2 has been used

clinically to enhance T cell immunity in patients with AIDS or cancer,

and blocking antibodies to the IL2 receptor are used to inhibit T cell

responses against transplanted tissues.22 In analogy to IL2, MLT has

also been used to enhance T cell immunity in patients with cancer.23

Perhaps, the ability of MLT to enhance production of inflammatory

cytokines from human monocytes/macrophages, including IL12,24–26 turns

the MLT/IL2 connection towards the enhancement of T cell immunity

rather than to formation of T regulatory cells.

http://ard.bmj.com/cgi/content/full/64/8/1109

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Not an MD