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Does melatonin play a disease-promoting role in rheumatoid arthritis?
Journal of Neuroimmunology 158 (2005) 106 – 111 www.elsevier.com/locate/jneuroim
Does melatonin play a disease-promoting role in rheumatoid arthritis? Georges J.M. Maestronia,*, Daniel P. Cardinalib, Ana I. Esquifinoc, S.R. Pandi-Perumald a
Center for Experimental Pathology, Cantonal Institute of Pathology, Via In Selva 24, P.O. Box 6601 Locarno, Switzerland b Departamento de Fisiologı´a, Facultad de Medicina, Universidad de Buenos Aires, 1121 Buenos Aires, Argentina c Departamento de Bioquı´mica y Biologı´a Molecular III, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain d Section of Sleep Medicine, Division of Clinical Neurophysiology and Epilepsy, Department of Neurology, College of Medicine, SUNY Downstate Medical Center, 450 Clarkson Avenue, Box 1213, Brooklyn, NY 11203-2098, USA Received 7 July 2004; received in revised form 16 August 2004; accepted 17 August 2004
Abstract The pineal neurohormone melatonin (MLT) has been widely shown to exert an immunostimulatory and antiapoptotic role, mainly by acting on Th cells and on T and B cell precursors, respectively. Thus, MLT might favor or promote autoimmune diseases by acting directly on immature and mature immunocompetent cells. In fact, preclinical and clinical evidence point to a disease-promoting role of MLT in rheumatoid arthritis (RA). MLT, whose concentration is increased in serum from RA patients, may act systemically or locally in the inflamed joints. The circadian secretion of MLT with a peak level during the night hours might be strictly correlated with the peculiar daily rhythmicity of the RA symptoms. In rat studies employing Freund’s complete mycobacterial adjuvant (FCA) as a model of rheumatoid arthritis, pinealectomized rats turned arthritic and exhibited a significantly less pronounced inflammatory response, which was restored to normal by a low MLT dose and was aggravated by a pharmacological MLT dose, that augmented the inflammatory and immune response. Continued investigation will refine our understanding of these observations, which will possibly translate into improved therapeutic approaches. D 2004 Elsevier B.V. All rights reserved. Keywords: Rheumatoid arthritis; Melatonin; Corticosteroids; T-helper 1; Inflammatory cytokines; Freund’s adjuvant arthritis; Circadian rhythms
1. Melatonin is an arm of the biologic clock affecting immune function The circadian production of the pineal neurohormone melatonin (MLT) synchronizes the organism in the photoperiod to optimize its seasonal adaptation and survival. The physiological mechanisms that may be affected by MLT include thermoregulation, reproduction, sleep, and immunity. With regard to the immune system, MLT may act on specific membrane receptors expressed on immunocompetent cells with MT2 receptors apparently playing the major role (Carrillo-Vico et al., 2003; Drazen and Nelson, 2001; Maestroni, 1999). Nuclear receptors have been also described in lymphocytes (Rafii-El-Idrissi et al., 1998; * Corresponding author. Tel.: +41 91 81 60791; fax: +41 91 81 60799. E-mail address: [email protected] (G.J.M. Maestroni). 0165-5728/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2004.08.015
Smirnov, 2001). MLT can stimulate the immune response and correct immunodeficiencies secondary to acute stress, viral diseases, or drug treatment. Binding of MLT to its specific receptors resulted in an upregulation of cytokine production and immune function (Maestroni, 1998). In general, the immunoenhancing action of MLT seems to be restricted to T-dependent antigens and most pronounced in immunodepressed situations. For example, MLT may completely counteract thymus involution and the immunological depression induced by stress events or glucocorticoid treatment (Maestroni and Conti, 1990) or restore depressed immunological functions after soft-tissue trauma and hemorrhagic shock (Wichmann et al., 1996a,b). The immunoenhancing action of MLT has been then confirmed and extended in a variety of animal species and in humans (Carrillo-Vico et al., 2004; Nelson and Demas, 1997; RafiiEl-Idrissi et al., 1998; Yellon et al., 1999) and birds
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(Carrillo-Vico et al., 2004; Kliger et al., 2000; Moore and Siopes, 2000; Nelson and Demas, 1997; Rafii-El-Idrissi et al., 1998; Yellon et al., 1999). In human peripheral blood mononuclear cells, MLT has been reported to stimulate the production of interleukin-2 (IL-2), interferon-gamma (IFN-g), and interleukin-6 (IL-6) but not that of interleukin-4 (IL-4; Garcia-Maurin˜o et al., 1997). More recently, human lymphocytes were shown to synthesize and release MLT, which in turn stimulated IL-2 production in an autocrine or paracrine fashion (Carrillo-Vico et al., 2004). Physiologically, the nocturnal MLT peak has been associated with high IFN-g/interleukin-10 (IL-10) ratio, i.e., the MLT rhythm positively correlated with the rhythmicity of T-helper cell-type 1/T-helper cell-type 2 ratio (Carrillo-Vico et al., 2004; Kliger et al., 2000; Moore and Siopes, 2000; Nelson and Demas, 1997; Petrovsky and Harrison, 1996, 1998; Rafii-El-Idrissi et al., 1998; Yellon et al., 1999). Most interestingly, reduction of MLT secretion was reported to parallel disease progression and to correlate with serum IL-12 levels in HIV-1-infected patients (Nunnari et al., 2003). In ischaemic stroke patients, an impaired nocturnal MLT excretion has been associated with impaired cell-mediated immunity and changes of lymphocyte subsets (Fiorina et al., 1999). In both humans and rats, the nocturnal increase in serum concentration of thymosin-a1 and thymulin seems to depend on MLT (Molinero et al., 2000). MLT can activate human monocytes and stimulate IL-1, IL-6, and IL-12 production (Barjavel et al., 1998; Fjaerly et al., 1999; Garcia-Maurin˜o et al., 1999, 2000; Lissoni et al., 1997). However, T lymphocytes also seem to be targets of MLT in mice (Hofbauer and Heufelder, 1996; Maestroni and Conti, 1990) and humans (Garcia-Maurin˜o et al., 1997; Guerrero et al., 1996). These human studies confirmed that MLT possesses important immunoenhancing properties and suggest that MLT may favor a T-helper celltype 1 response. We reported that MLT might rescue haemopoiesis in mice transplanted with Lewis Lung Carcinoma (LLC) and treated with cancer chemotherapeutic compounds (Maestroni et al., 1994a). This effect apparently involved the endogenous release of granulocyte/macrophage colonystimulating factor and MLT-induced opioid cytokines (Maestroni et al., 1994a,b; Maestroni, 1999). More recent reports confirmed the protective effect of MLT in rats and mice against the haemopoietic toxicity of various cytotoxic drugs (Anwar et al., 1998; Rapozzi et al., 1998). Besides its protective effect against cytotoxic drugs, exogenous MLT was reported to enhance the production of NK cells and monocytes in the bone marrow of mice (Currier et al., 2000). Most interestingly, melatonin inhibits B-cell apoptosis, and that phenomenon is restricted mainly to the earliest stages of B-cell differentiation. This suggested that melatonin might act as a checkpoint regulator in early B-cell development and may even contribute to diurnal rhythm in B-lymphocyte production. MLT-induced suppression of apoptosis in the enormous quantities of B cells generated
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by the bone marrow of the mouse daily (Osmond, 1980) could have important pharmacological implications. While it appears that melatonin treatment would result in a greater quantity of B lymphocytes produced (potentially strengthening humoral immunity), such excessive suppression could permit genetically aberrant B cells to evade the normal deletion process (resulting in apoptosis) with defective B cells entering the circulation as preneoplastic or autoreactive cells. Interestingly, in another report, the presence of high levels of MLT was found to correlate with tonsillar hypertrophy in paediatric patients (Lopez-Gonzales et al., 1998). Taken together, these findings point to an important immunoenhancing and haemopoietic effect of MLT—the relative mechanism might depend on the ability of MLT to enhance the production of haemopoietic cytokines (Maestroni et al., 1994a) as well as on its reported antioxidant and antiapoptotic action (Reiter and Maestroni, 1999).
2. Rheumatoid arthritis is a systemic rheumatoid disease Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis and affects about 1% of the population, in a female/male ratio of 2.5:1. The disease can occur at any age, but it is most common among those aged 40–70 years. The geographic distribution of rheumatoid arthritis is worldwide, with a notably low prevalence in rural areas (Goodson and Symmons, 2002; Reginster, 2002). Although it initially presents as a symmetrical polyarticular synovitis with prominent hand involvement, rheumatoid arthritis has multiple potential systemic manifestations. The clinical course of the disorder is extremely variable, ranging from mild, self-limiting arthritis to rapidly progressive multisystem inflammation with profound morbidity and mortality. Fever and weight loss can be part of the acute symptoms, while splenomegaly, vasculitis, neutropenia, and amyloidosis are some of the disease’s complications, which may occur in patients with long-standing disease (Bowman, 2002; Reginster, 2002; Youssef and Tavill, 2002). As for other systemic rheumatic diseases such as juvenile idiopathic arthritis, systemic lupus erythematosus, and systemic sclerosis, the etiology remains unclear. A thin lining layer of synoviocytes under which blood vessels compose the normal synovium, fat cells, fibroblasts and rare mononuclear cells are embedded in an extracellular matrix. The picture is quite different for inflamed synovium of patients with RA, in which there is an extensive infiltration of macrophages and T and B cells into the sublining region. In many such patients, large perivascular cellular aggregates, which have a well-organized follicle-like structure that proliferates in a network of follicular DC, form (Kim and Berek, 2000). This inflammation may result in hyperplasia of synoviocytes, infiltration of mononuclear cells, neoangiogenesis, pannus formation, and finally joint
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destruction. Despite intensive efforts, we still have no clear idea regarding what induces inflammation in synovial membrane. Significant progress has been made in identifying genetic and environmental components of the pathogenesis of these diseases that determine severity and outcome. Genetic components include functional alterations of genes active in apoptosis antigen recognition, adhesion, and cytokine production. Most of the immune abnormalities pertain to B and T lymphocytes and myeloid cells. In addition to genetic factors, environmental factors must also play an important role, as illustrated by the observations that transfer of stem cells from patients to healthy recipients did not result in disease in the recipient. Environmental factors include external triggers such as smoking and infection, as well as internal triggers such as changes in neuroendocrine factors such as those associated with pregnancy. Also, stress events or an inadequate response to them might play a role in promoting RA. Neuroendocrine hormones triggered during stress may lead to immune disregulation or altered cytokine production, resulting in autoimmune diseases or decreased host defense (Elenkov and Chrousos, 1999; Elenkov et al., 2000).
3. A role of MLT is demonstrable in rat adjuvant arthritis Efforts to develop safer and more effective treatments for rheumatoid arthritis rely heavily on the availability of suitable animal models (Bendele, 2001). Among these models, a rat’s adjuvant arthritis is widely employed (Whitehouse, 1988). Hallmarks of this rat model are reliable onset and progression of easily measurable, polyarticular inflammation, marked bone resorption, and periosteal bone proliferation. Induction of adjuvant disease can be done with either Freund’s complete adjuvant (FCA) supplemented with mycobacterium or by injecting synthetic adjuvants (Bendele, 2001; Whitehouse, 1988). The pathogenesis for development of adjuvant disease following injection of mycobacterial preparations is not fully understood, although a cross-reactivity of mycobacterial wall antigens with cartilage proteoglycans occurs. The use of the adjuvant’s arthritis model offers an opportunity to study pathological changes in a variety of tissues other than the joints. Among these, central nervous system (CNS) changes are most relevant (Dantzer, 2001; Johnson, 2002; Larson, 2002). The major objective of our work during the last years has been to examine the effect of MLT on several circadian correlates at both the preclinical and the acute phases of arthritis in rats (Cardinali and Esquifino, 2003). Pretreatment for 11 days with a pharmacological dose of MLT (100 Ag) affected some aspects of the early phase of the immune response elicited by FCA injection. Cell proliferation in rat submaxillary lymph nodes and spleen during the immune reaction exhibited a pineal-dependent
diurnal rhythmicity, as it was reduced by pinealectomy or pineal sympathetic denervation (Cardinali et al., 1996, 1997). This effect was counteracted by pharmacological MLT doses. MLT also restored the reduced amplitude in diurnal rhythms of lymph node or splenic norepinephrine synthesis and lymph node acetylcholine (ACh) synthesis. Further examination of MLT activity on circadian rhythmicity of cell proliferation in submaxillary lymph nodes and spleen at the clinical phase of arthritis was conducted in young and old Sprague–Dawley rats (Cardinali et al., 1998). Pineal MLT content was measured, as well as the efficacy of MLT treatment to recover modified circadian rhythmicity of submaxillary lymph node and splenic cell proliferation and neurotransmitter synthesis. After daily injections of pharmacological amounts of MLT (10 or 100 Ag) in the evening, the treatment restored the inflammatory response in old rats to the level found in young animals. In young rats, an inflammation-promoting effect of the higher dose of MLT was demonstrated. The results were compatible with an age-dependent, significant depression of pineal MLT synthesis during adjuvant-induced arthritis and with decreased amplitude of circadian rhythms in immune cell proliferation and autonomic activity in lymph nodes and spleen at the clinical phase of the disease. This picture was generally counteracted by MLT injection, mainly in old rats (Cardinali et al., 1998). Physiological circulating levels of MLT at midnight in rats are about 90 pg/ml in rats (Chan et al., 1984), while the MLT levels achieved within 15 min after the systemic administration of a 100-Ag dose are about 2000 greater (Raynaud et al., 1993), with a half-life of about 20 min. We recently examined whether the administration of MLT to pinealectomized rats in a way that reproduced the plasma values and daily rhythm of endogenous MLT could affect immune responses during arthritis development (Cardinali et al., 2004). Pinealectomized rats exhibited a significantly less pronounced inflammatory response, which was restored to normal by physiological MLT administration. The physiological doses of MLT employed were effective to counteract the impaired response of lymph node cell proliferation seen in pinealectomized rats. It must be noted that the pharmacological effect of melatonin on the immune response may not always be beneficial, particularly in young subjects. In autoimmune arthritis developed in mice with type II rat collagen, melatonin administration (1 mg/kg) induced a more severe arthritis. Accordingly, pinealectomy in two strains of mice immunized with rat type II collagen reduced severity of the arthritis as shown by a slower onset of the disease, a less severe course of the disease (reduced clinical scores), and reduced serum levels of anticollagen II antibodies (Hansson et al., 1992, 1993). Using a 100-Ag dose of melatonin, an inflammation-promoting effect could be demonstrated in young rats injected with FCA. In contrast, melatonin administration (10 or 100 Ag) to old rats restored the inflammatory response in hind paws of FCA-injected rats to
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levels found in young rats (Cardinali et al., 1998). Therefore, high levels of melatonin in young animals may stimulate the immune system and cause exacerbation of both autoimmune collagen II and mycobacterial arthritis.
4. MLT role in RA In this context, MLT might be involved in an autoimmune disease like RA by virtue of its ability to boost Th cells responses, counteract the immunosuppressive effect of corticosteroids, and inhibit apoptosis of B and, perhaps, T cell precursors. Thus, factors that enhance endogenous MLT production might play a role in the etiology of RA. It is interesting to note that the geographical distribution of RA shows a north–south gradient, with higher latitudes being associated with an increased incidence and severity of RA (Cooper and Stroehla, 2003). The increased season-associated variability in the photoperiod might mean enhanced MLT production especially during the long winter nights. In addition, the clinical symptoms of RA show a circadian variation with joint stiffness and pain being more prominent in the early morning. Consistently, human proinflammatory cytokine production exhibits a diurnal rhythmicity with peak levels during the night and early morning at a time when plasma cortisol is lowest (Petrovsky and Harrison, 1998). The existence of a causal relationship between plasma cortisol and production of inflammatory cytokines is suggested by the finding that administration of cortisone acetate at physiological doses results in a corresponding reduction in proinflammatory cytokine production (Straub and Cutolo, 2001). An inappropriate low secretion of cortisol is a further typical feature of the inflammatory disease in RA patients (Straub and Cutolo, 2001). It is interesting to underline that, generally, MLT shows an anticorticosteroid effect (Maestroni et al., 1986). Hence, the clinical symptoms of RA synovitis such as joint morning stiffness and gelling might be related to the circadian rhythm of MLT synthesis and release. A recent clinical study strongly supports a close relationship between MLT production and IL-12 and NO production by macrophages from RA patients (Cutolo et al., 1999). We also found that RA patients have higher nocturnal serum concentration of melatonin than healthy controls do. Also, the area under the curve of the circadian rhythm of melatonin is significantly higher in RA patients. More interestingly, we confirmed this finding in another study comparing the serum concentration of MLT in RA patients from a northern European country (Estonia) with that shown by matched RA patients from a southern European country (Italy). The circadian serum concentrations of MLT (and TNFa) were significantly higher in northern than in southern patients. In addition, MLT and TNF-a concentrations in both patient groups were increased when compared with the sex- and age-matched controls (Cutolo et al., in press). The MLT–RA relationship might explain why clinical symptoms of rheumatoid synovitis are more
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evident in the early morning. Another interesting observation was that macrophages infiltrating the synovial fluid of RA patients showed specific MLT binding sites. Most interestingly, MLT was also present at high concentrations in the synovial fluid (Maestroni et al., 2002b). Taken together, these findings suggest that MLT might play a promoting role in RA. Hence, inhibition of MLT synthesis and or action by specific antagonist might be of therapeutic value. As the significant differences were observed especially at the beginning and end of the dark period and in RA patients living in a northern country in which the seasonal variation in the photoperiod is extreme (Cutolo et al., in press; Maestroni et al., 2002a,b), it might be that RA patients have a defect in the multisynaptic pathway connecting the retina and the retinohypothalamic tract (RHT) to the pineal gland. Alternatively, MLT production in RA patients might be boosted by excessive amounts of inflammatory cytokine produced during the ongoing autoimmune reaction. It has, in fact, been demonstrated that IFN-g may enhance MLT production in pineal organ cultures (Withyachumnarnkul et al., 1990). In this case, the ongoing autoimmune response in RA patients would reinforce itself also via increased MLT production in a vicious circle. Furthermore, due to the antiapoptotic action of MLT at the level of B and T cell precursors (Maestroni, 2001), excessive levels of this hormone might promote survival of autoreactive cells clones. Clearly, these are speculations that need further studies to be proved or disproved. The focus of this review is on MLT; however, other hormones show a circadian rhythmicity and have also been involved in immune regulation. It is the case of the hypothalamo–pituitary–gonadal axis with sexual steroids as its end products. Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone as natural immune suppressors. As a matter of fact, it is well known that RA and other autoimmune diseases show a dramatic higher prevalence in females, and androgen administration has been shown to influence RA (Cutolo et al., 2002). In addition, the sympathetic nervous system, which drives the circadian pacemaker situated in the suprachiasmatic nuclei, is also deeply implicated in immune regulation, and adrenergic disorders have been involved in RA (Elenkov et al., 2000). Thus, the emerging picture appears extremely complex all the more because MLT may affect or be influenced by these neuroendocrine and neural factors. In any case, the available evidence about the MLT involvement in the pathogenesis of RA is quite sound and might offer interesting and innovative therapeutic possibilities.
References Anwar, M.M., Mahfouz, H.A., Sayed, A.S., 1998. Potential protective effects of melatonin on bone marrow of rats exposed to cytotoxic drugs. Comp. Biochem. Physiol. 119, 493 – 591.
110
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Barjavel, M.J., Mamdouh, Z., Raghbate, N., Bakouche, O., 1998. Differential expression of the melatonin receptor in human monocytes. J. Immunol. 160, 1191 – 1197. Bendele, A.M., 2001. Animal models of rheumatoid arthritis. J. Musculoskel Neuron Interact. 1, 377 – 385. Bowman, S.J., 2002. Hematological manifestations of rheumatoid arthritis. Scand. J. Rheumatol. 31, 251 – 259. Cardinali, D.P., Esquifino, A.I., 2003. Circadian disorganization in experimental arthritis. NeuroSignals 12, 267 – 282. Cardinali, D.P., Cutrera, R.A., Castrillon, P., Esquifino, A.I., 1996. Diurnal rhythms in ornithine decarboxylase activity and norepinephrine and acetylcholine synthesis of rat submaxillary lymph nodes: effect of pinealectomy, superior cervical ganglionectomy and melatonin replacement. Neuroimmunomodulation 3, 102 – 111. Cardinali, D.P., Cutrera, R.A., Garcia Bonacho, M., Esquifino, A.I., 1997. Effect of pinealectomy, superior cervical ganglionectomy and melatonin treatment on 24-hour rhythms in ornithine decarboxylase and tyrosine hydroxylase activities of rat spleen. J. Pineal Res. 22, 210 – 220. Cardinali, D.P., Brusco, L.I., Garcia Bonacho, M., Esquifino, A.I., 1998. Effect of melatonin on 24-hour rhythms of ornithine decarboxylase activity and norepinephrine and acetylcholine synthesis in submaxillary lymph nodes and spleen of young and aged rats. Neuroendocrinology 67, 349 – 362. ´ a, A.P., Cano, P., Esquifino, A.I., 2004. Melatonin Cardinali, D.P., GarcU role in experimental arthritis. Current Drug Targets. Immune, Endocrine and Metabolic Disorders 4, 1 – 22. Carrillo-Vico, A., Garcia-Perganeda, A., Naji, L., Calvo, J.R., Romero, M.P., Guerrero, J.M., 2003. Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system. Cell. Mol. Life Sci. 60, 2272 – 2278. Carrillo-Vico, A., Calvo, J.R., Abreu, P., Lardone, P.J., Garcia-Maurino, S., Reiter, R.J., Guerrero, J.M., 2004. Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and/or paracrine substance. FASEB J. 18, 537 – 539. Chan, M.Y., Pang, S.F., Tang, P.L., Brown, G.M., 1984. Studies on the kinetics of melatonin and N-acetylserotonin in the rat at mid-light and mid-dark. J. Pineal Res. 1, 227 – 236. Chan, M.Y., Pang, S.F., Tang, P.L., Brown, G.M., 1984. Studies on the kinetics of melatonin and N-acetylserotonin in the rat at mid-light and mid-dark. J. Pineal Res. 1, 227 – 236. Cooper, G.S., Stroehla, B.C., 2003. The epidemiology of autoimmune diseases. Autoimmun. Rev. 2, 119 – 125. Currier, N.L., Sun, L.Z., Miller, S.C., 2000. Exogenous melatonin: qualitative enhancement in vivo of cells mediating non-specific immunity. J. Neuroimmunol. 104, 101 – 108. Cutolo, M., Villaggio, B., Candido, F., Valenti, S., Giusti, M., Felli, L., Sulli, A., Accardo, S., 1999. Melatonin influences interleukin-12 and nitric oxide production by primary cultures of rheumatoid synovial macrophages and THP-1 cells. Ann. N.Y. Acad. Sci. 876, 246 – 254. Cutolo, M., Villaggio, B., Craviotto, C., Pizzorini, C., Seriolo, B., Sulli, A., 2002. Sex hormones and rheumatoid arthritis. Autoimmun. Rev. 5, 284 – 289. Cutolo, M., Maestroni, G., Otsa, K., Aakre, O., Villaggio, B., Capellino, S., Montagna, P., Fazzuoli, L., Veldi, T., Pets, T., Hertens, E., Sulli, A., 2004. Circadian melatonin and cortisol levels in rheumatoid arthritis patients in winter time: a north and south Europe comparison. Ann. Rheum. Dis. (in press). Dantzer, R., 2001. Cytokine-induced sickness behavior: mechanisms and implications. Ann. N.Y. Acad. Sci. 933, 222 – 234. Drazen, D.L., Nelson, R.J., 2001. Melatonin receptor subtype MT2 (Mel 1b) and not mt1 (Mel 1a) is associated with melatonin-induced enhancement of cell-mediated and humoral immunity. Neuroendocrinology 74, 178 – 184. Elenkov, I.J., Chrousos, G.P., 1999. Stress hormones, Th1/Th2 patterns, pro/anti-inflammatory cytokines and susceptibility to disease. Trends Endocrinol. Metab. 10, 359 – 368.
Elenkov, I.J., Wilder, R.L., Chrousos, G.P., Vizi, S., 2000. The sympathetic nervean integrative interface between two supersystems: the brain and the immune system. Pharmacol. Rev. 52, 595 – 638. Fiorina, P., Lattuada, G., Silvestrini, C., Ponari, O., Dall’Aglio, P., 1999. Disruption of nocturnal melatonin rhythm and immunological involvement in ischaemic stroke patients. Scand. J. Immunol. 50, 228 – 231. Fjaerly, O., Lund, T., Osterud, B., 1999. The effect of melatonin on cellular activation processes in human blood. J. Pineal Res. 26, 50 – 55. Garcia-Maurin˜o, S., Gonzales-Haba, M.G., Calvo, J.R., Rafii-El-Idrissi, M., Sanchez-Margalet, V., Goberna, R., Guerrero, J.M., 1997. Melatonin enhances IL-2, Il-6, and IFN-g production by human circulating CD4+ cells. J. Immunol. 159, 574 – 581. Garcia-Maurin˜o, S., Pozo, D., Carillo-Vico, A., Calvo, J.R., Guerero, J.M., 1999. Melatonin activates Th1 lymphocytes by increasing IL-12 production. Life Sci. 65, 2143 – 2150. Garcia-Maurin˜o, S., Pozo, D., Calvo, J.R., Guerrero, J.M., 2000. Correlation between nuclear melatonin receptor expression and enhanced cytokine production in human lymphocytic and monocytic cell lines. J. Pineal Res. 29, 129 – 137. Goodson, N., Symmons, D., 2002. Rheumatoid arthritis in women: still associated with an increased mortality. Ann. Rheum. Dis. 61, 955 – 956. Guerrero, J.-M., Garcia-Maurino, S., Gil-Haba, M., Rafii-El-Idrissi, M., Pozo, D., Garcia-Perganeda, A., Calvo, J.R., 1996. Mechanisms of action on the human immune system: membrane receptors versus nuclear receptors. In: Maestroni, G.J.M., Conti, A., Reiter, R.J. (Eds.), Therapeutic Potential of the Pineal Hormone Melatonin, Frontiers of Hormone Research, vol. 23. Karger, Basel, pp. 43 – 52. Hansson, I., Holmdahl, R., Mattsson, R., 1992. The pineal hormone melatonin exaggerates development of collagen-induced arthritis in mice. J. Neuroimmunol. 39, 23 – 31. Hansson, I., Holmdahl, R., Mattsson, R., 1993. Pinealectomy ameliorates collagen II-induced arthritis in mice. Clin. Exp. Immunol. 92, 432 – 436. Hofbauer, L.C., Heufelder, A.E., 1996. Endocrinology meets immunology: T lymphocytes as novel targets for melatonin. Eur. J. Endocrinol. 134, 424 – 425. Kim, H.J., Berek, C., 2000. B cells in rheumatoid arthritis. Arthritis Res. 2, 126 – 131. Kliger, C.A., Gehad, A.E., Hulet, R.M., Roush, W.B., Lillehoj, H.S., Mashaly, M.M., 2000. Effects of photoperiod and melatonin on lymphocyte activities in male broiler chickens. Poult. Sci. 79, 18 – 25. Johnson, R.W., 2002. The concept of sickness behavior: a brief chronological account of four key discoveries. Vet. Immunol. Immunopathol. 87, 443 – 450. Larson, S.J., 2002. Behavioral and motivational effects of immune-system activation. J. Gen. Psych. 129, 401 – 414. Lissoni, P., Rovelli, F., Brivio, F., Pittalis, S., Maestroni, G.J.M., Fumagalli, L., 1997. In vivo study of the modulatory effect of the pineal hormone melatonin on interleukin-12 secretion in response to interleukin-2. Int. J. Thymol. 5, 482 – 486. Lopez-Gonzales, M.A., Guerrero, J.M., Ceballo Pedraja, J.M., Delgado, M., 1998. Melatonin in palate tonsils with recurrent acute tonsillitis and tonsillar hyperthrophy. Acta Otorrinolaringol. Esp. 49, 625 – 628. Maestroni, G.J.M., 1998. The photoperiod transducer melatonin and the immunehematopoietic system. J. Photochem. Photobiol. 43, 186 – 192. Maestroni, G.J., 1999. Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer. Adv. Exp. Med. Biol. 467, 217 – 226. Maestroni, G.J.M., 2001. The immunotherapeutic potential of melatonin. Exp. Opin. Invest. Drugs 10, 467 – 476. Maestroni, G.J.M., Conti, A., 1990. The pineal neurohormone melatonin stimulates activated CD4+, Thy-1+ cells to release opioid agonist(s) with immunoenhancing and anti-stress properties. J. Neuroimmunol. 28, 167 – 176. Maestroni, G.J.M., Conti, A., Pierpaoli, W., 1986. Role of the pineal gland in immunity. Circadian synthesis and release of melatonin modulates
G.J.M. Maestroni et al. / Journal of Neuroimmunology 158 (2005) 106–111 the antibody response and antagonize the imunosuppressive effect of corticosterone. J. Neuroimmunol. 13, 19 – 30. Maestroni, G.J.M., Conti, A., Lissoni, P., 1994a. Colony-stimulating activity and hematopoietic rescue from cancer chemotherapy compounds are induced by melatonin via endogenous interleukin 4. Cancer Res. 54, 4740 – 4743. Maestroni, G.J.M., Covacci, V., Conti, A., 1994b. Hematopoietic rescue via T-cell-dependent, endogenous GM-CSF by the pineal neurohormone melatonin in tumor bearing mice. Cancer Res. 54, 2429 – 2432. Maestroni, G.J., Sulli, A., Pizzorni, C., Villaggio, B., Cutolo, M., 2002a. Melatonin in rheumatoid arthritis: a disease-promoting and modulating hormone?. Clin. Exp. Rheumatol. 20, 872 – 873. Maestroni, G.J., Sulli, A., Pizzorni, C., Villaggio, B., Cutolo, M., 2002b. Melatonin in rheumatoid arthritis: synovial macrophages show melatonin receptors. Ann. N.Y. Acad. Sci. 966, 271 – 275. Molinero, P., Soutto, M., benot, S., Hmadcha, A., Guerrero, J.M., 2000. Melatonin is responsible for the nocturlan increase observed inserum and thymus of thymosin alpha1 and thymulin concentrations: observations in rats and humans. J. Neuroimmunol. 103, 180 – 188. Moore, C.B., Siopes, T.D., 2000. Effects of lighting conditions and melatonin supplementation on the cellular and humoral immune responses in Japanese quail Coturnix coturnix japonica. Gen. Comp. Endocrinol. 119, 95 – 104. Nelson, R.J., Demas, G.E., 1997. Role of melatonin in mediating seasonal energetic and immunologic adaptations. Brain Res. Bull. 44, 423 – 430. Nunnari, G., Nigro, L., Palermo, F., Leto, D., Pomerantz, R.J., Cacopardo, B., 2003. Reduction of serum melatonin levels in HIV-1-infected individuals’ parallel disease progression: correlation with serum interleukin-12 levels. Infection 31, 379 – 382. Osmond, D.G., 1980. The contribution of bone marrow to the economy of the lymphoid system. Monogr. Allergy 16, 157 – 172. Petrovsky, N., Harrison, L., 1996. Diurnal rhythmicity of human cytokine production. A dynamic disequilibrium in T helper cell type 1/T helper cell type 2 balance. J. Immunol. 158, 5163 – 5168. Petrovsky, N., Harrison, L., 1998. The chronobiology of human cytokine production. Int. Rev. Immunol. 16, 635 – 649. Rafii-El-Idrissi, M., Calvo, J.R., Harmouch, A., Garcia-Maurino, S., Guerrero, J.M., 1998. Specific binding of melatonin by purified cell
111
nuclei from spleen and thymus of the rat. J. Neuroimmunol. 86, 190 – 197. Rapozzi, V., Zorzet, S., Comelli, M., Mavelli, I., Perissin, L., Giraldi, T., 1998. Melatonin decreases bone marrow and lymphatic toxicity of adrymycin in mice bearing TLX5 lymphoma. Life Sci. 63, 171 – 1713. Raynaud, F., Mauviard, F., Geoffriau, M., Claustrat, B., Pevet, P., 1993. Plasma 6-hydroxymelatonin, 6-sulfatoxymelatonin and melatonin kinetics after melatonin administration to rats. Biol. Signals 2, 358 – 366. Reginster, J.Y., 2002. The prevalence and burden of arthritis. Rheumatology. (Oxf.) 41 (Suppl. 1), 3 – 6. Reiter, R.J., Maestroni, G.J.M., 1999. Melatonin in relation to the antioxidative defense and immune systems: possible impications for cell and organ transplantation. J. Mol. Med. 77, 36 – 39. Smirnov, A.N., 2001. Nuclear melatonin receptors. Biochemistry (Mosc.) 66, 19 – 26. Straub, R.H., Cutolo, M., 2001. Involvement of the hypothalamic-pituitaryadrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: viewpoint based on a systemic pathogenetic role. Arthritis Rheum. 44, 493 – 507. Whitehouse, M.W., 1988. Adjuvant-induced polyarthritis in rats. In: Greenwald, R.A., Diamad, H.S. (Eds.), Handbook of Animal Models for the Rheumatic Diseases. CRC Press, New York, pp. 3 – 16. Wichmann, M.W., Haisken, J.M., Ayala, A., Chaudry, I.H., 1996a. Melatonin administration following hemorrhagic shock decreases mortality from subsequent septic challenge. J. Surg. Res. 65, 109 – 114. Wichmann, M.W., Zellweger, R., Ayala, A., Chaudry, I.H., 1996b. Melatonin administration attenuates depressed immune functions trauma-hemorrhage. J. Surg. Res. 63, 256 – 262. Withyachumnarnkul, B., Nonaka, K.O., Santana, C., Attia, A.M., Reiter, R.J., 1990. Interferon-gamma modulates melatonin production in rat pineal gland in organ culture. J. Interf. Res. 10, 403 – 411. Yellon, S.M., Teasley, L.A., fagoaga, O.R., Nguyen, H.C., Truong, H.N., Nehlsen-Cannarella, L., 1999. Role of photoperiod and the pineal gland in T cell-dependent humoral immune reactivity in the Siberian hamster. J. Pineal Res. 27, 243 – 248. Youssef, W.I., Tavill, A.S., 2002. Connective tissue diseases and the liver. J. Clin. Gastroenterol. 35, 345 – 349.
Does melatonin play a disease-promoting role in rheumatoid arthritis? Georges J.M. Maestronia,*, Daniel P. Cardinalib, Ana I. Esquifinoc, S.R. Pandi-Perumald a
Center for Experimental Pathology, Cantonal Institute of Pathology, Via In Selva 24, P.O. Box 6601 Locarno, Switzerland b Departamento de Fisiologı´a, Facultad de Medicina, Universidad de Buenos Aires, 1121 Buenos Aires, Argentina c Departamento de Bioquı´mica y Biologı´a Molecular III, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain d Section of Sleep Medicine, Division of Clinical Neurophysiology and Epilepsy, Department of Neurology, College of Medicine, SUNY Downstate Medical Center, 450 Clarkson Avenue, Box 1213, Brooklyn, NY 11203-2098, USA Received 7 July 2004; received in revised form 16 August 2004; accepted 17 August 2004
Abstract The pineal neurohormone melatonin (MLT) has been widely shown to exert an immunostimulatory and antiapoptotic role, mainly by acting on Th cells and on T and B cell precursors, respectively. Thus, MLT might favor or promote autoimmune diseases by acting directly on immature and mature immunocompetent cells. In fact, preclinical and clinical evidence point to a disease-promoting role of MLT in rheumatoid arthritis (RA). MLT, whose concentration is increased in serum from RA patients, may act systemically or locally in the inflamed joints. The circadian secretion of MLT with a peak level during the night hours might be strictly correlated with the peculiar daily rhythmicity of the RA symptoms. In rat studies employing Freund’s complete mycobacterial adjuvant (FCA) as a model of rheumatoid arthritis, pinealectomized rats turned arthritic and exhibited a significantly less pronounced inflammatory response, which was restored to normal by a low MLT dose and was aggravated by a pharmacological MLT dose, that augmented the inflammatory and immune response. Continued investigation will refine our understanding of these observations, which will possibly translate into improved therapeutic approaches. D 2004 Elsevier B.V. All rights reserved. Keywords: Rheumatoid arthritis; Melatonin; Corticosteroids; T-helper 1; Inflammatory cytokines; Freund’s adjuvant arthritis; Circadian rhythms
1. Melatonin is an arm of the biologic clock affecting immune function The circadian production of the pineal neurohormone melatonin (MLT) synchronizes the organism in the photoperiod to optimize its seasonal adaptation and survival. The physiological mechanisms that may be affected by MLT include thermoregulation, reproduction, sleep, and immunity. With regard to the immune system, MLT may act on specific membrane receptors expressed on immunocompetent cells with MT2 receptors apparently playing the major role (Carrillo-Vico et al., 2003; Drazen and Nelson, 2001; Maestroni, 1999). Nuclear receptors have been also described in lymphocytes (Rafii-El-Idrissi et al., 1998; * Corresponding author. Tel.: +41 91 81 60791; fax: +41 91 81 60799. E-mail address: [email protected] (G.J.M. Maestroni). 0165-5728/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2004.08.015
Smirnov, 2001). MLT can stimulate the immune response and correct immunodeficiencies secondary to acute stress, viral diseases, or drug treatment. Binding of MLT to its specific receptors resulted in an upregulation of cytokine production and immune function (Maestroni, 1998). In general, the immunoenhancing action of MLT seems to be restricted to T-dependent antigens and most pronounced in immunodepressed situations. For example, MLT may completely counteract thymus involution and the immunological depression induced by stress events or glucocorticoid treatment (Maestroni and Conti, 1990) or restore depressed immunological functions after soft-tissue trauma and hemorrhagic shock (Wichmann et al., 1996a,b). The immunoenhancing action of MLT has been then confirmed and extended in a variety of animal species and in humans (Carrillo-Vico et al., 2004; Nelson and Demas, 1997; RafiiEl-Idrissi et al., 1998; Yellon et al., 1999) and birds
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(Carrillo-Vico et al., 2004; Kliger et al., 2000; Moore and Siopes, 2000; Nelson and Demas, 1997; Rafii-El-Idrissi et al., 1998; Yellon et al., 1999). In human peripheral blood mononuclear cells, MLT has been reported to stimulate the production of interleukin-2 (IL-2), interferon-gamma (IFN-g), and interleukin-6 (IL-6) but not that of interleukin-4 (IL-4; Garcia-Maurin˜o et al., 1997). More recently, human lymphocytes were shown to synthesize and release MLT, which in turn stimulated IL-2 production in an autocrine or paracrine fashion (Carrillo-Vico et al., 2004). Physiologically, the nocturnal MLT peak has been associated with high IFN-g/interleukin-10 (IL-10) ratio, i.e., the MLT rhythm positively correlated with the rhythmicity of T-helper cell-type 1/T-helper cell-type 2 ratio (Carrillo-Vico et al., 2004; Kliger et al., 2000; Moore and Siopes, 2000; Nelson and Demas, 1997; Petrovsky and Harrison, 1996, 1998; Rafii-El-Idrissi et al., 1998; Yellon et al., 1999). Most interestingly, reduction of MLT secretion was reported to parallel disease progression and to correlate with serum IL-12 levels in HIV-1-infected patients (Nunnari et al., 2003). In ischaemic stroke patients, an impaired nocturnal MLT excretion has been associated with impaired cell-mediated immunity and changes of lymphocyte subsets (Fiorina et al., 1999). In both humans and rats, the nocturnal increase in serum concentration of thymosin-a1 and thymulin seems to depend on MLT (Molinero et al., 2000). MLT can activate human monocytes and stimulate IL-1, IL-6, and IL-12 production (Barjavel et al., 1998; Fjaerly et al., 1999; Garcia-Maurin˜o et al., 1999, 2000; Lissoni et al., 1997). However, T lymphocytes also seem to be targets of MLT in mice (Hofbauer and Heufelder, 1996; Maestroni and Conti, 1990) and humans (Garcia-Maurin˜o et al., 1997; Guerrero et al., 1996). These human studies confirmed that MLT possesses important immunoenhancing properties and suggest that MLT may favor a T-helper celltype 1 response. We reported that MLT might rescue haemopoiesis in mice transplanted with Lewis Lung Carcinoma (LLC) and treated with cancer chemotherapeutic compounds (Maestroni et al., 1994a). This effect apparently involved the endogenous release of granulocyte/macrophage colonystimulating factor and MLT-induced opioid cytokines (Maestroni et al., 1994a,b; Maestroni, 1999). More recent reports confirmed the protective effect of MLT in rats and mice against the haemopoietic toxicity of various cytotoxic drugs (Anwar et al., 1998; Rapozzi et al., 1998). Besides its protective effect against cytotoxic drugs, exogenous MLT was reported to enhance the production of NK cells and monocytes in the bone marrow of mice (Currier et al., 2000). Most interestingly, melatonin inhibits B-cell apoptosis, and that phenomenon is restricted mainly to the earliest stages of B-cell differentiation. This suggested that melatonin might act as a checkpoint regulator in early B-cell development and may even contribute to diurnal rhythm in B-lymphocyte production. MLT-induced suppression of apoptosis in the enormous quantities of B cells generated
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by the bone marrow of the mouse daily (Osmond, 1980) could have important pharmacological implications. While it appears that melatonin treatment would result in a greater quantity of B lymphocytes produced (potentially strengthening humoral immunity), such excessive suppression could permit genetically aberrant B cells to evade the normal deletion process (resulting in apoptosis) with defective B cells entering the circulation as preneoplastic or autoreactive cells. Interestingly, in another report, the presence of high levels of MLT was found to correlate with tonsillar hypertrophy in paediatric patients (Lopez-Gonzales et al., 1998). Taken together, these findings point to an important immunoenhancing and haemopoietic effect of MLT—the relative mechanism might depend on the ability of MLT to enhance the production of haemopoietic cytokines (Maestroni et al., 1994a) as well as on its reported antioxidant and antiapoptotic action (Reiter and Maestroni, 1999).
2. Rheumatoid arthritis is a systemic rheumatoid disease Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis and affects about 1% of the population, in a female/male ratio of 2.5:1. The disease can occur at any age, but it is most common among those aged 40–70 years. The geographic distribution of rheumatoid arthritis is worldwide, with a notably low prevalence in rural areas (Goodson and Symmons, 2002; Reginster, 2002). Although it initially presents as a symmetrical polyarticular synovitis with prominent hand involvement, rheumatoid arthritis has multiple potential systemic manifestations. The clinical course of the disorder is extremely variable, ranging from mild, self-limiting arthritis to rapidly progressive multisystem inflammation with profound morbidity and mortality. Fever and weight loss can be part of the acute symptoms, while splenomegaly, vasculitis, neutropenia, and amyloidosis are some of the disease’s complications, which may occur in patients with long-standing disease (Bowman, 2002; Reginster, 2002; Youssef and Tavill, 2002). As for other systemic rheumatic diseases such as juvenile idiopathic arthritis, systemic lupus erythematosus, and systemic sclerosis, the etiology remains unclear. A thin lining layer of synoviocytes under which blood vessels compose the normal synovium, fat cells, fibroblasts and rare mononuclear cells are embedded in an extracellular matrix. The picture is quite different for inflamed synovium of patients with RA, in which there is an extensive infiltration of macrophages and T and B cells into the sublining region. In many such patients, large perivascular cellular aggregates, which have a well-organized follicle-like structure that proliferates in a network of follicular DC, form (Kim and Berek, 2000). This inflammation may result in hyperplasia of synoviocytes, infiltration of mononuclear cells, neoangiogenesis, pannus formation, and finally joint
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destruction. Despite intensive efforts, we still have no clear idea regarding what induces inflammation in synovial membrane. Significant progress has been made in identifying genetic and environmental components of the pathogenesis of these diseases that determine severity and outcome. Genetic components include functional alterations of genes active in apoptosis antigen recognition, adhesion, and cytokine production. Most of the immune abnormalities pertain to B and T lymphocytes and myeloid cells. In addition to genetic factors, environmental factors must also play an important role, as illustrated by the observations that transfer of stem cells from patients to healthy recipients did not result in disease in the recipient. Environmental factors include external triggers such as smoking and infection, as well as internal triggers such as changes in neuroendocrine factors such as those associated with pregnancy. Also, stress events or an inadequate response to them might play a role in promoting RA. Neuroendocrine hormones triggered during stress may lead to immune disregulation or altered cytokine production, resulting in autoimmune diseases or decreased host defense (Elenkov and Chrousos, 1999; Elenkov et al., 2000).
3. A role of MLT is demonstrable in rat adjuvant arthritis Efforts to develop safer and more effective treatments for rheumatoid arthritis rely heavily on the availability of suitable animal models (Bendele, 2001). Among these models, a rat’s adjuvant arthritis is widely employed (Whitehouse, 1988). Hallmarks of this rat model are reliable onset and progression of easily measurable, polyarticular inflammation, marked bone resorption, and periosteal bone proliferation. Induction of adjuvant disease can be done with either Freund’s complete adjuvant (FCA) supplemented with mycobacterium or by injecting synthetic adjuvants (Bendele, 2001; Whitehouse, 1988). The pathogenesis for development of adjuvant disease following injection of mycobacterial preparations is not fully understood, although a cross-reactivity of mycobacterial wall antigens with cartilage proteoglycans occurs. The use of the adjuvant’s arthritis model offers an opportunity to study pathological changes in a variety of tissues other than the joints. Among these, central nervous system (CNS) changes are most relevant (Dantzer, 2001; Johnson, 2002; Larson, 2002). The major objective of our work during the last years has been to examine the effect of MLT on several circadian correlates at both the preclinical and the acute phases of arthritis in rats (Cardinali and Esquifino, 2003). Pretreatment for 11 days with a pharmacological dose of MLT (100 Ag) affected some aspects of the early phase of the immune response elicited by FCA injection. Cell proliferation in rat submaxillary lymph nodes and spleen during the immune reaction exhibited a pineal-dependent
diurnal rhythmicity, as it was reduced by pinealectomy or pineal sympathetic denervation (Cardinali et al., 1996, 1997). This effect was counteracted by pharmacological MLT doses. MLT also restored the reduced amplitude in diurnal rhythms of lymph node or splenic norepinephrine synthesis and lymph node acetylcholine (ACh) synthesis. Further examination of MLT activity on circadian rhythmicity of cell proliferation in submaxillary lymph nodes and spleen at the clinical phase of arthritis was conducted in young and old Sprague–Dawley rats (Cardinali et al., 1998). Pineal MLT content was measured, as well as the efficacy of MLT treatment to recover modified circadian rhythmicity of submaxillary lymph node and splenic cell proliferation and neurotransmitter synthesis. After daily injections of pharmacological amounts of MLT (10 or 100 Ag) in the evening, the treatment restored the inflammatory response in old rats to the level found in young animals. In young rats, an inflammation-promoting effect of the higher dose of MLT was demonstrated. The results were compatible with an age-dependent, significant depression of pineal MLT synthesis during adjuvant-induced arthritis and with decreased amplitude of circadian rhythms in immune cell proliferation and autonomic activity in lymph nodes and spleen at the clinical phase of the disease. This picture was generally counteracted by MLT injection, mainly in old rats (Cardinali et al., 1998). Physiological circulating levels of MLT at midnight in rats are about 90 pg/ml in rats (Chan et al., 1984), while the MLT levels achieved within 15 min after the systemic administration of a 100-Ag dose are about 2000 greater (Raynaud et al., 1993), with a half-life of about 20 min. We recently examined whether the administration of MLT to pinealectomized rats in a way that reproduced the plasma values and daily rhythm of endogenous MLT could affect immune responses during arthritis development (Cardinali et al., 2004). Pinealectomized rats exhibited a significantly less pronounced inflammatory response, which was restored to normal by physiological MLT administration. The physiological doses of MLT employed were effective to counteract the impaired response of lymph node cell proliferation seen in pinealectomized rats. It must be noted that the pharmacological effect of melatonin on the immune response may not always be beneficial, particularly in young subjects. In autoimmune arthritis developed in mice with type II rat collagen, melatonin administration (1 mg/kg) induced a more severe arthritis. Accordingly, pinealectomy in two strains of mice immunized with rat type II collagen reduced severity of the arthritis as shown by a slower onset of the disease, a less severe course of the disease (reduced clinical scores), and reduced serum levels of anticollagen II antibodies (Hansson et al., 1992, 1993). Using a 100-Ag dose of melatonin, an inflammation-promoting effect could be demonstrated in young rats injected with FCA. In contrast, melatonin administration (10 or 100 Ag) to old rats restored the inflammatory response in hind paws of FCA-injected rats to
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levels found in young rats (Cardinali et al., 1998). Therefore, high levels of melatonin in young animals may stimulate the immune system and cause exacerbation of both autoimmune collagen II and mycobacterial arthritis.
4. MLT role in RA In this context, MLT might be involved in an autoimmune disease like RA by virtue of its ability to boost Th cells responses, counteract the immunosuppressive effect of corticosteroids, and inhibit apoptosis of B and, perhaps, T cell precursors. Thus, factors that enhance endogenous MLT production might play a role in the etiology of RA. It is interesting to note that the geographical distribution of RA shows a north–south gradient, with higher latitudes being associated with an increased incidence and severity of RA (Cooper and Stroehla, 2003). The increased season-associated variability in the photoperiod might mean enhanced MLT production especially during the long winter nights. In addition, the clinical symptoms of RA show a circadian variation with joint stiffness and pain being more prominent in the early morning. Consistently, human proinflammatory cytokine production exhibits a diurnal rhythmicity with peak levels during the night and early morning at a time when plasma cortisol is lowest (Petrovsky and Harrison, 1998). The existence of a causal relationship between plasma cortisol and production of inflammatory cytokines is suggested by the finding that administration of cortisone acetate at physiological doses results in a corresponding reduction in proinflammatory cytokine production (Straub and Cutolo, 2001). An inappropriate low secretion of cortisol is a further typical feature of the inflammatory disease in RA patients (Straub and Cutolo, 2001). It is interesting to underline that, generally, MLT shows an anticorticosteroid effect (Maestroni et al., 1986). Hence, the clinical symptoms of RA synovitis such as joint morning stiffness and gelling might be related to the circadian rhythm of MLT synthesis and release. A recent clinical study strongly supports a close relationship between MLT production and IL-12 and NO production by macrophages from RA patients (Cutolo et al., 1999). We also found that RA patients have higher nocturnal serum concentration of melatonin than healthy controls do. Also, the area under the curve of the circadian rhythm of melatonin is significantly higher in RA patients. More interestingly, we confirmed this finding in another study comparing the serum concentration of MLT in RA patients from a northern European country (Estonia) with that shown by matched RA patients from a southern European country (Italy). The circadian serum concentrations of MLT (and TNFa) were significantly higher in northern than in southern patients. In addition, MLT and TNF-a concentrations in both patient groups were increased when compared with the sex- and age-matched controls (Cutolo et al., in press). The MLT–RA relationship might explain why clinical symptoms of rheumatoid synovitis are more
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evident in the early morning. Another interesting observation was that macrophages infiltrating the synovial fluid of RA patients showed specific MLT binding sites. Most interestingly, MLT was also present at high concentrations in the synovial fluid (Maestroni et al., 2002b). Taken together, these findings suggest that MLT might play a promoting role in RA. Hence, inhibition of MLT synthesis and or action by specific antagonist might be of therapeutic value. As the significant differences were observed especially at the beginning and end of the dark period and in RA patients living in a northern country in which the seasonal variation in the photoperiod is extreme (Cutolo et al., in press; Maestroni et al., 2002a,b), it might be that RA patients have a defect in the multisynaptic pathway connecting the retina and the retinohypothalamic tract (RHT) to the pineal gland. Alternatively, MLT production in RA patients might be boosted by excessive amounts of inflammatory cytokine produced during the ongoing autoimmune reaction. It has, in fact, been demonstrated that IFN-g may enhance MLT production in pineal organ cultures (Withyachumnarnkul et al., 1990). In this case, the ongoing autoimmune response in RA patients would reinforce itself also via increased MLT production in a vicious circle. Furthermore, due to the antiapoptotic action of MLT at the level of B and T cell precursors (Maestroni, 2001), excessive levels of this hormone might promote survival of autoreactive cells clones. Clearly, these are speculations that need further studies to be proved or disproved. The focus of this review is on MLT; however, other hormones show a circadian rhythmicity and have also been involved in immune regulation. It is the case of the hypothalamo–pituitary–gonadal axis with sexual steroids as its end products. Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone as natural immune suppressors. As a matter of fact, it is well known that RA and other autoimmune diseases show a dramatic higher prevalence in females, and androgen administration has been shown to influence RA (Cutolo et al., 2002). In addition, the sympathetic nervous system, which drives the circadian pacemaker situated in the suprachiasmatic nuclei, is also deeply implicated in immune regulation, and adrenergic disorders have been involved in RA (Elenkov et al., 2000). Thus, the emerging picture appears extremely complex all the more because MLT may affect or be influenced by these neuroendocrine and neural factors. In any case, the available evidence about the MLT involvement in the pathogenesis of RA is quite sound and might offer interesting and innovative therapeutic possibilities.
References Anwar, M.M., Mahfouz, H.A., Sayed, A.S., 1998. Potential protective effects of melatonin on bone marrow of rats exposed to cytotoxic drugs. Comp. Biochem. Physiol. 119, 493 – 591.
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Barjavel, M.J., Mamdouh, Z., Raghbate, N., Bakouche, O., 1998. Differential expression of the melatonin receptor in human monocytes. J. Immunol. 160, 1191 – 1197. Bendele, A.M., 2001. Animal models of rheumatoid arthritis. J. Musculoskel Neuron Interact. 1, 377 – 385. Bowman, S.J., 2002. Hematological manifestations of rheumatoid arthritis. Scand. J. Rheumatol. 31, 251 – 259. Cardinali, D.P., Esquifino, A.I., 2003. Circadian disorganization in experimental arthritis. NeuroSignals 12, 267 – 282. Cardinali, D.P., Cutrera, R.A., Castrillon, P., Esquifino, A.I., 1996. Diurnal rhythms in ornithine decarboxylase activity and norepinephrine and acetylcholine synthesis of rat submaxillary lymph nodes: effect of pinealectomy, superior cervical ganglionectomy and melatonin replacement. Neuroimmunomodulation 3, 102 – 111. Cardinali, D.P., Cutrera, R.A., Garcia Bonacho, M., Esquifino, A.I., 1997. Effect of pinealectomy, superior cervical ganglionectomy and melatonin treatment on 24-hour rhythms in ornithine decarboxylase and tyrosine hydroxylase activities of rat spleen. J. Pineal Res. 22, 210 – 220. Cardinali, D.P., Brusco, L.I., Garcia Bonacho, M., Esquifino, A.I., 1998. Effect of melatonin on 24-hour rhythms of ornithine decarboxylase activity and norepinephrine and acetylcholine synthesis in submaxillary lymph nodes and spleen of young and aged rats. Neuroendocrinology 67, 349 – 362. ´ a, A.P., Cano, P., Esquifino, A.I., 2004. Melatonin Cardinali, D.P., GarcU role in experimental arthritis. Current Drug Targets. Immune, Endocrine and Metabolic Disorders 4, 1 – 22. Carrillo-Vico, A., Garcia-Perganeda, A., Naji, L., Calvo, J.R., Romero, M.P., Guerrero, J.M., 2003. Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system. Cell. Mol. Life Sci. 60, 2272 – 2278. Carrillo-Vico, A., Calvo, J.R., Abreu, P., Lardone, P.J., Garcia-Maurino, S., Reiter, R.J., Guerrero, J.M., 2004. Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and/or paracrine substance. FASEB J. 18, 537 – 539. Chan, M.Y., Pang, S.F., Tang, P.L., Brown, G.M., 1984. Studies on the kinetics of melatonin and N-acetylserotonin in the rat at mid-light and mid-dark. J. Pineal Res. 1, 227 – 236. Chan, M.Y., Pang, S.F., Tang, P.L., Brown, G.M., 1984. Studies on the kinetics of melatonin and N-acetylserotonin in the rat at mid-light and mid-dark. J. Pineal Res. 1, 227 – 236. Cooper, G.S., Stroehla, B.C., 2003. The epidemiology of autoimmune diseases. Autoimmun. Rev. 2, 119 – 125. Currier, N.L., Sun, L.Z., Miller, S.C., 2000. Exogenous melatonin: qualitative enhancement in vivo of cells mediating non-specific immunity. J. Neuroimmunol. 104, 101 – 108. Cutolo, M., Villaggio, B., Candido, F., Valenti, S., Giusti, M., Felli, L., Sulli, A., Accardo, S., 1999. Melatonin influences interleukin-12 and nitric oxide production by primary cultures of rheumatoid synovial macrophages and THP-1 cells. Ann. N.Y. Acad. Sci. 876, 246 – 254. Cutolo, M., Villaggio, B., Craviotto, C., Pizzorini, C., Seriolo, B., Sulli, A., 2002. Sex hormones and rheumatoid arthritis. Autoimmun. Rev. 5, 284 – 289. Cutolo, M., Maestroni, G., Otsa, K., Aakre, O., Villaggio, B., Capellino, S., Montagna, P., Fazzuoli, L., Veldi, T., Pets, T., Hertens, E., Sulli, A., 2004. Circadian melatonin and cortisol levels in rheumatoid arthritis patients in winter time: a north and south Europe comparison. Ann. Rheum. Dis. (in press). Dantzer, R., 2001. Cytokine-induced sickness behavior: mechanisms and implications. Ann. N.Y. Acad. Sci. 933, 222 – 234. Drazen, D.L., Nelson, R.J., 2001. Melatonin receptor subtype MT2 (Mel 1b) and not mt1 (Mel 1a) is associated with melatonin-induced enhancement of cell-mediated and humoral immunity. Neuroendocrinology 74, 178 – 184. Elenkov, I.J., Chrousos, G.P., 1999. Stress hormones, Th1/Th2 patterns, pro/anti-inflammatory cytokines and susceptibility to disease. Trends Endocrinol. Metab. 10, 359 – 368.
Elenkov, I.J., Wilder, R.L., Chrousos, G.P., Vizi, S., 2000. The sympathetic nervean integrative interface between two supersystems: the brain and the immune system. Pharmacol. Rev. 52, 595 – 638. Fiorina, P., Lattuada, G., Silvestrini, C., Ponari, O., Dall’Aglio, P., 1999. Disruption of nocturnal melatonin rhythm and immunological involvement in ischaemic stroke patients. Scand. J. Immunol. 50, 228 – 231. Fjaerly, O., Lund, T., Osterud, B., 1999. The effect of melatonin on cellular activation processes in human blood. J. Pineal Res. 26, 50 – 55. Garcia-Maurin˜o, S., Gonzales-Haba, M.G., Calvo, J.R., Rafii-El-Idrissi, M., Sanchez-Margalet, V., Goberna, R., Guerrero, J.M., 1997. Melatonin enhances IL-2, Il-6, and IFN-g production by human circulating CD4+ cells. J. Immunol. 159, 574 – 581. Garcia-Maurin˜o, S., Pozo, D., Carillo-Vico, A., Calvo, J.R., Guerero, J.M., 1999. Melatonin activates Th1 lymphocytes by increasing IL-12 production. Life Sci. 65, 2143 – 2150. Garcia-Maurin˜o, S., Pozo, D., Calvo, J.R., Guerrero, J.M., 2000. Correlation between nuclear melatonin receptor expression and enhanced cytokine production in human lymphocytic and monocytic cell lines. J. Pineal Res. 29, 129 – 137. Goodson, N., Symmons, D., 2002. Rheumatoid arthritis in women: still associated with an increased mortality. Ann. Rheum. Dis. 61, 955 – 956. Guerrero, J.-M., Garcia-Maurino, S., Gil-Haba, M., Rafii-El-Idrissi, M., Pozo, D., Garcia-Perganeda, A., Calvo, J.R., 1996. Mechanisms of action on the human immune system: membrane receptors versus nuclear receptors. In: Maestroni, G.J.M., Conti, A., Reiter, R.J. (Eds.), Therapeutic Potential of the Pineal Hormone Melatonin, Frontiers of Hormone Research, vol. 23. Karger, Basel, pp. 43 – 52. Hansson, I., Holmdahl, R., Mattsson, R., 1992. The pineal hormone melatonin exaggerates development of collagen-induced arthritis in mice. J. Neuroimmunol. 39, 23 – 31. Hansson, I., Holmdahl, R., Mattsson, R., 1993. Pinealectomy ameliorates collagen II-induced arthritis in mice. Clin. Exp. Immunol. 92, 432 – 436. Hofbauer, L.C., Heufelder, A.E., 1996. Endocrinology meets immunology: T lymphocytes as novel targets for melatonin. Eur. J. Endocrinol. 134, 424 – 425. Kim, H.J., Berek, C., 2000. B cells in rheumatoid arthritis. Arthritis Res. 2, 126 – 131. Kliger, C.A., Gehad, A.E., Hulet, R.M., Roush, W.B., Lillehoj, H.S., Mashaly, M.M., 2000. Effects of photoperiod and melatonin on lymphocyte activities in male broiler chickens. Poult. Sci. 79, 18 – 25. Johnson, R.W., 2002. The concept of sickness behavior: a brief chronological account of four key discoveries. Vet. Immunol. Immunopathol. 87, 443 – 450. Larson, S.J., 2002. Behavioral and motivational effects of immune-system activation. J. Gen. Psych. 129, 401 – 414. Lissoni, P., Rovelli, F., Brivio, F., Pittalis, S., Maestroni, G.J.M., Fumagalli, L., 1997. In vivo study of the modulatory effect of the pineal hormone melatonin on interleukin-12 secretion in response to interleukin-2. Int. J. Thymol. 5, 482 – 486. Lopez-Gonzales, M.A., Guerrero, J.M., Ceballo Pedraja, J.M., Delgado, M., 1998. Melatonin in palate tonsils with recurrent acute tonsillitis and tonsillar hyperthrophy. Acta Otorrinolaringol. Esp. 49, 625 – 628. Maestroni, G.J.M., 1998. The photoperiod transducer melatonin and the immunehematopoietic system. J. Photochem. Photobiol. 43, 186 – 192. Maestroni, G.J., 1999. Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer. Adv. Exp. Med. Biol. 467, 217 – 226. Maestroni, G.J.M., 2001. The immunotherapeutic potential of melatonin. Exp. Opin. Invest. Drugs 10, 467 – 476. Maestroni, G.J.M., Conti, A., 1990. The pineal neurohormone melatonin stimulates activated CD4+, Thy-1+ cells to release opioid agonist(s) with immunoenhancing and anti-stress properties. J. Neuroimmunol. 28, 167 – 176. Maestroni, G.J.M., Conti, A., Pierpaoli, W., 1986. Role of the pineal gland in immunity. Circadian synthesis and release of melatonin modulates
G.J.M. Maestroni et al. / Journal of Neuroimmunology 158 (2005) 106–111 the antibody response and antagonize the imunosuppressive effect of corticosterone. J. Neuroimmunol. 13, 19 – 30. Maestroni, G.J.M., Conti, A., Lissoni, P., 1994a. Colony-stimulating activity and hematopoietic rescue from cancer chemotherapy compounds are induced by melatonin via endogenous interleukin 4. Cancer Res. 54, 4740 – 4743. Maestroni, G.J.M., Covacci, V., Conti, A., 1994b. Hematopoietic rescue via T-cell-dependent, endogenous GM-CSF by the pineal neurohormone melatonin in tumor bearing mice. Cancer Res. 54, 2429 – 2432. Maestroni, G.J., Sulli, A., Pizzorni, C., Villaggio, B., Cutolo, M., 2002a. Melatonin in rheumatoid arthritis: a disease-promoting and modulating hormone?. Clin. Exp. Rheumatol. 20, 872 – 873. Maestroni, G.J., Sulli, A., Pizzorni, C., Villaggio, B., Cutolo, M., 2002b. Melatonin in rheumatoid arthritis: synovial macrophages show melatonin receptors. Ann. N.Y. Acad. Sci. 966, 271 – 275. Molinero, P., Soutto, M., benot, S., Hmadcha, A., Guerrero, J.M., 2000. Melatonin is responsible for the nocturlan increase observed inserum and thymus of thymosin alpha1 and thymulin concentrations: observations in rats and humans. J. Neuroimmunol. 103, 180 – 188. Moore, C.B., Siopes, T.D., 2000. Effects of lighting conditions and melatonin supplementation on the cellular and humoral immune responses in Japanese quail Coturnix coturnix japonica. Gen. Comp. Endocrinol. 119, 95 – 104. Nelson, R.J., Demas, G.E., 1997. Role of melatonin in mediating seasonal energetic and immunologic adaptations. Brain Res. Bull. 44, 423 – 430. Nunnari, G., Nigro, L., Palermo, F., Leto, D., Pomerantz, R.J., Cacopardo, B., 2003. Reduction of serum melatonin levels in HIV-1-infected individuals’ parallel disease progression: correlation with serum interleukin-12 levels. Infection 31, 379 – 382. Osmond, D.G., 1980. The contribution of bone marrow to the economy of the lymphoid system. Monogr. Allergy 16, 157 – 172. Petrovsky, N., Harrison, L., 1996. Diurnal rhythmicity of human cytokine production. A dynamic disequilibrium in T helper cell type 1/T helper cell type 2 balance. J. Immunol. 158, 5163 – 5168. Petrovsky, N., Harrison, L., 1998. The chronobiology of human cytokine production. Int. Rev. Immunol. 16, 635 – 649. Rafii-El-Idrissi, M., Calvo, J.R., Harmouch, A., Garcia-Maurino, S., Guerrero, J.M., 1998. Specific binding of melatonin by purified cell
111
nuclei from spleen and thymus of the rat. J. Neuroimmunol. 86, 190 – 197. Rapozzi, V., Zorzet, S., Comelli, M., Mavelli, I., Perissin, L., Giraldi, T., 1998. Melatonin decreases bone marrow and lymphatic toxicity of adrymycin in mice bearing TLX5 lymphoma. Life Sci. 63, 171 – 1713. Raynaud, F., Mauviard, F., Geoffriau, M., Claustrat, B., Pevet, P., 1993. Plasma 6-hydroxymelatonin, 6-sulfatoxymelatonin and melatonin kinetics after melatonin administration to rats. Biol. Signals 2, 358 – 366. Reginster, J.Y., 2002. The prevalence and burden of arthritis. Rheumatology. (Oxf.) 41 (Suppl. 1), 3 – 6. Reiter, R.J., Maestroni, G.J.M., 1999. Melatonin in relation to the antioxidative defense and immune systems: possible impications for cell and organ transplantation. J. Mol. Med. 77, 36 – 39. Smirnov, A.N., 2001. Nuclear melatonin receptors. Biochemistry (Mosc.) 66, 19 – 26. Straub, R.H., Cutolo, M., 2001. Involvement of the hypothalamic-pituitaryadrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: viewpoint based on a systemic pathogenetic role. Arthritis Rheum. 44, 493 – 507. Whitehouse, M.W., 1988. Adjuvant-induced polyarthritis in rats. In: Greenwald, R.A., Diamad, H.S. (Eds.), Handbook of Animal Models for the Rheumatic Diseases. CRC Press, New York, pp. 3 – 16. Wichmann, M.W., Haisken, J.M., Ayala, A., Chaudry, I.H., 1996a. Melatonin administration following hemorrhagic shock decreases mortality from subsequent septic challenge. J. Surg. Res. 65, 109 – 114. Wichmann, M.W., Zellweger, R., Ayala, A., Chaudry, I.H., 1996b. Melatonin administration attenuates depressed immune functions trauma-hemorrhage. J. Surg. Res. 63, 256 – 262. Withyachumnarnkul, B., Nonaka, K.O., Santana, C., Attia, A.M., Reiter, R.J., 1990. Interferon-gamma modulates melatonin production in rat pineal gland in organ culture. J. Interf. Res. 10, 403 – 411. Yellon, S.M., Teasley, L.A., fagoaga, O.R., Nguyen, H.C., Truong, H.N., Nehlsen-Cannarella, L., 1999. Role of photoperiod and the pineal gland in T cell-dependent humoral immune reactivity in the Siberian hamster. J. Pineal Res. 27, 243 – 248. Youssef, W.I., Tavill, A.S., 2002. Connective tissue diseases and the liver. J. Clin. Gastroenterol. 35, 345 – 349.