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Bidirectional communication between the pineal gland and the immune system1,2
Krystyna Skwarlo-Sonta, Pawel Majewski, Magdalena Markowska, Ruslan Oblap, and Bozenna Olszanska
Abstract: The pineal gland is a vertebrate neuroendocrine organ converting environmental photoperiodic information into a biochemical message (melatonin) that subsequently regulates the activity of numerous target tissues after its release into the bloodstream. A phylogenetically conserved feature is increased melatonin synthesis during darkness, even though there are differences between mammals and birds in the regulation of rhythmic pinealocyte function. Membrane-bound melatonin receptors are found in many peripheral organs, including lymphoid glands and immune cells, from which melatonin receptor genes have been characterized and cloned. The expression of melatonin receptor genes within the immune system shows species and organ specificity. The pineal gland, via the rhythmical synthesis and release of melatonin, influences the development and function of the immune system, although the postreceptor signal transduction system is poorly understood. Circulating messages produced by activated immune cells are reciprocally perceived by the pineal gland and provide feedback for the regulation of pineal function. The pineal gland and the immune system are, therefore, reciprocally linked by bidirectional communication. Key words: pineal gland, melatonin, immunity, melatonin receptors, melatonin receptor transcripts. Rsum : Chez les vertbrs, la glande pinale est un organe neuroendocrinien traduisant linformation photopriodique environnementale en un message biochimique (mlatonine) qui rgule lactivit de nombreux tissus cibles aprs sa libration dans la circulation sanguine. Une caractristique conserve phylogntiquement est laugmentation de la synthse de la mlatonine durant lobscurit, mme sil existe des diffrences entre les mammifres et les oiseaux au niveau de la rgulation de la fonction rythmique des pinalocytes. Des rcepteurs membranaires de la mlatonine sont prsents dans de nombreux organes priphriques, incluant les glandes lymphodes et les cellules immunitaires, do les gnes des rcepteurs de la mlatonine ont t caractrises et clons. Lexpression des gnes des rcepteurs de la mlatonine dans le systme immunitaire montre une spcificit despce et dorgane. La glande pinale, par lintermdiaire de la synthse et de la libration rythmiques de la mlatonine, influence le dveloppement et la fonction du systme immunitaire; toutefois, le mcanisme de traduction des signaux post-rcepteurs nest pas encore lucid. Les messages produits par les cellules immunitaires actives sont perus rciproquement par la glande pinale et par un effet de rtroaction rgulent la fonction pinale. La glande pinale et le systme immunitaire sont, par consquent, rciproquement lis par une communication bidirectionnelle. Mots cls : glande pinale, mlatonine, immunit, rcepteurs de la mlatonine, transcrits des rcepteurs de la mlatonine. [Traduit par la Rdaction] Skwarlo-Sonta et al. 349
Received 22 July 2002. Published on the NRC Research Press Web site at http://cjpp.nrc.ca on 2 April 2003. K. Skwarlo-Sonta,3 P. Majewski, and M. Markowska. Department of Vertebrate Physiology, Faculty of Biology, Warsaw University, Poland. R. Oblap4 and B. Olszanska. Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, n/Warsaw, Poland.
1 2
This paper has undergone the journals usual peer review process. Presented at a Designated Meeting of the Physiological Society on Comparative Neuroscience and Comparative Physiology, University of Central Lancashire, Preston, U.K., May 2002. 3 Corresponding author (e-mail: kss@biol.uw.edu.pl). 4 Present address: Institute of Agriecology and Biotechnology, Ukrainian Academy of Agricultural Sciences, 12 Metrologicheskaya str. Kyiv 03143, Ukraine.
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343 Fig. 1. Melatonin biosynthesis pathway. The graphs on the right show typical relations between the respective enzymes, light conditions, and melatonin levels in the pineal glands (according to Reiter 1993; Bernard et al. 1999).
Introduction
In vertebrates, the pineal gland is a neuroendocrine organ that converts external (photoperiodic) information into an internal (hormonal) message for the regulation of peripheral target sites linked through the bloodstream (Reiter 1989). Melatonin is the hormone produced by the pineal gland and its synthesis is characteristically increased nocturnally or during darkness. The magnitude and duration of the nocturnal increase in melatonin synthesis is dependent upon the length of the dark phase of the photoperiodic cycle and it acts as a clock and calendar for the entrainment of other biological activities. It occurs in all vertebrate species, regardless of their diurnal or nocturnal locomotor activity, and it is thus a message of darkness and not of the rest or sleep period (Illnerova et al. 2000). In mammals, pineal melatonin synthesis is driven by a circadian oscillator in the hypothalamic suprachiasmatic nucleus (SCN), through a multisynaptic neural pathway that includes sympathetic nerve terminals that project from the superior cervical ganglia to the pineal gland. Nocturnal elevations in noradrenergic (NA) stimulation, via - and 1adrenergic receptors on pinealocytes, increase the intracellular concentration of cyclic adenosine monophosphate (cAMP), which in turn activates arylalkylamine N-acetyltransferase (AA-NAT; EC 2.3.1.87) (Vacas et al. 1985), the penultimate and key enzyme in the synthesis of melatonin from tryptophan (Takahashi et al. 1989). Melatonin concentrations in the pineal and in blood therefore reflect the circadian rhythm in pineal AA-NAT activity (Fig. 1), which is also positively correlated with pinealocyte levels of cAMP (Falcon and Begay 1998). A similar circadian rhythm in melatonin production is also present in birds, although avian pinealocytes have direct photosensitivity (Collin et al. 1989; Cassone and Natesan 1997). Avian pinealocytes, moreover, have 2 -adrenergic receptors rather than - and 1-receptors and their activation occurs in the light phase, causing a decrease in pineal cAMP content, an inhibition of AA-NAT activity and a diminished release of melatonin (Zatz and Mullen 1988) (Fig. 2).
Singh 2000), as well as the number of cells mediating nonspecific immunity (Currier et al. 2000). It has therefore been proposed as a putative anticancer therapy (for review see Lissoni 1999). Melatonin is also thought to have an emergency role in the immune system when it is activated by antigen stimulation (e.g., during infection). In this situation the actions of melatonin are, however, dependent on the species, experimental paradigm, and the immune function measured. For instance, it is generally accepted that cell-mediated immune function is increased in rodents by exogenous melatonin treatment (Maestroni et al. 1987; Demas and Nelson 1998) and is suppressed by pinealectomy (Haldar and Singh 2001). Contrary findings have, however, been presented by Provinciali et al. (1997). Melatonin treatment similarly elevates both cellular and humoral immune responses in quail (Haldar and Singh 2000; Moore and Siopes 2000), but blood levels of immune regulators are unaffected in young chickens by melatonin treatment and pinealectomy, although diurnal rhythms of these regulators are modified (Rosolowska-Huszcz et al. 1992, Skwarlo-Sonta et al. 1992). Furthermore, while melatonin has been reported to directly induce the proliferation of human peripheral blood mononuclear cells (PBMCs) in vitro (Kuhlwein and Irwin 2001), Rogers et al. (1997) found it inhibited PBMC proliferation. Similarly, melatonin has been reported to inhibit (Di Stefano et al. 1994), stimulate (Garcia-Maurino et al. 2000), or have no effect (Kuhlwein and Irwin 2001) on the synthesis of interferon- (IFN-) by human PBMCs in vitro. The relation between melatonin and the immune system is, therefore, complex. Activated immune cells in rodents (Maestroni et al. 1987, 1988) and chickens (Dziwinski et al. 1999) also synthesize opioid-like substances as part of the immune response following melatonin treatment. This mechanism is probably responsible for the antistress (Maestroni et al. 1988), antiviral
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Fig. 2. Adrenergic regulation of melatonin synthesis in mammalian and avian pinealocytes. In mammals, noradrenaline (NA) release from sympathetic nerve terminals occurs in the dark. NA binding to - and 1 -adrenergic receptors on pinealocytes stimulates cAMP formation, which in turn activates AA-NAT, increasing melatonin levels (Vacas et al. 1985). In birds, NA release occurs in the light. NA binding to 2 -adrenergic receptors on pinealocytes inhibits cAMP formation, blocking AA-NAT activity and decreasing melatonin levels (Collin et al. 1989; Zatz and Mullen 1988).
(Ben-Nathan et al. 1994), and hematopoietic actions of melatonin (Maestroni 1999). Melatonin is also immunoprotective in chickens, since it modifies the development of experimental peritonitis (induced by an injection of thioglycolate) by reducing the number of peritoneal leukocytes (Skwarlo-Sonta et al. 2002b). An antiinflammatory action of melatonin has also been demonstrated in rats (Cuzzocrea et al. 1998). Immune tissues are therefore target sites for melatonin, and these effects are likely to be receptor mediated.
and MT2, and are members of the G-protein-coupled receptor superfamily (Dubocovich 1995). In addition to membrane binding sites, melatonin binding to the RZR/ROR orphan nuclear receptor superfamily has also been demonstrated in the rat spleen and thymus (RafiiEl-Idrissi et al. 1998). These nuclear receptors are thought to mediate some of effects of melatonin on cytokine production, cell proliferation and oncostasis (Garcia-Maurino et al. 2000; Steinhilbert et al. 1995; Winczyk et al. 2001).
Skwarlo-Sonta et al. Table 1. Membrane-bound melatonin receptors within the immune system. (A) Organs Source Thymus Rat Duck Chicken Bursa of Fabricius Duck Chicken Spleen Hamster Mouse Rat Guinea pig Chicken Reference Lopez-Gonzales et al. 1993 Martin-Cacao et al. 1993 Poon et al. 1994 Skwarlo-Sonta et al. 1994 Liu and Pang 1992 Skwarlo-Sonta et al. 1994 Niels 1989 Yu et al. 1991 Yu et al. 1991 Yu et al. 1991 Poon and Pang 1992 Yu et al. 1991 Pang and Pang 1992 Skwarlo-Sonta et al. 1994 Yu et al. 1991 Wang et al. 1993 Poon et al. 1993 Yu et al. 1991 Wang et al. 1993 Reference Lopez-Gonzalez et al. 1992 Guerrero et al. 1994 Barjavel et al. 1998 Garcia-Perganeda et al. 1999
345 Fig. 3. Presence of melatonin receptor transcripts in chicken lymphoid glands. Hi-Line chickens of both sexes obtained from a local hatchery were kept from hatch under controlled conditions (12 h light:12 h dark). Thymus, bursa of Fabricius, and spleen were isolated from 1- and 2-week-old chickens; thymocytes and splenocytes were separated from the respective glands, as described previously (Markowska et al. 2001). Total RNA was isolated using the InViSorb RNA kit II (InViTec GmbH, Berlin, Germany) according to manufacturers protocol and used for RTPCR. In brief, the material was lysed with the lysing solution, the DNA was removed with the sorbent, and the RNA was purified by phenol and chloroform extraction and precipitated with isopropanol. The RNA thus obtained was devoid of DNA contamination when tested by PCR. The primers for the melatonin receptor sequences were designed according to the published chick sequences: Mel1a (acc. No. U 31 821), Mel1b (acc. No. U 30 609), and Mel1c (acc. No. U 31 820). Primers were synthesized by InViTec GmbH; the sequence and RTPCR conditions were as described in Oblap and Olszanska (2001). The identity of the RTPCR products was attested by their size and by endonuclease restriction (Oblap and Olszanska 2001). NC, negative control without template DNA; M, molecular weight standard (100 bp DNA ladder, Promega); T, thymus; S, spleen; BF, bursa of Fabricius.
Pigeon
Duck Quail (B) Cells Source Lymphocytes Human Granulocytes Human Monocytes Human Peritoneal macrophages Mouse
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Can. J. Physiol. Pharmacol. Vol. 81, 2003 Table 2. Expression of melatonin receptor transcripts in the chicken immune and central nervous system. One-week-old (female/male) Material Thymus Bursa of Fabricius Spleen Brain hemispheres Hypothalamus Thymocytes Splenocytes Mel1a / / / nd/++ nd/++ nd nd Mel1b / ++ +/+++ +/+ + nd/++ nd/++ nd nd Mel1c +/+++ / + / + nd/++ nd/++ nd nd Two-week-old (female/male) Mel1a / / / nd/++ nd/++ / / Mel1b ++++/++++ ++++/++++ ++/ ++ nd/++ nd/++ + / ++ +++/ +++ Mel1c ++++/++++ + ++/+ ++ ++++/++++ nd/++ nd/++ ++ /++++ +++/ + +
Note: The data represent RTPCR results obtained for two female and two male birds, except for CNS tissues, where only two males were examined. Total RNA from the tissues of an individual bird was isolated and RTPCR was performed with the individual RNA samples once (+ or ) or twice (++, , or +) for each RNA sample. + and represent a result of a single RTPCR (positive or negative). nd, not determined.
by luzindole, an antagonist of membrane-bound melatonin receptors (Markowska et al. 2001, 2002). Melatonin similarly inhibits forskolin- and vasoactive intestinal peptide induced cAMP formation in chicken splenocytes (Markowska et al. 2002). It is therefore likely that melatonin acts through membrane-bound Mel1c and (or) Mel1b subtypes (see Fig. 3 and Table 2), coupled with G proteins, to modulate avian immune function.
an important role for IL-1 in the immune system pineal axis. Moreover, systemic inflammation induced by an i.p. injection of LPS induces IL-1 gene expression in the pineal gland, whereas expression of the cytokines that counterregulate IL-1 activity (e.g., IL-1 receptor agonist, IL-10, and IL-13) (Wong et al. 1997) is limited. In addition to direct actions on pinealocytes, cytokines and other immune factors may regulate pineal function by indirect actions on pineal glial cells. The presence of cytokine receptors in glial cells of the CNS (Brzezinski 1997) supports this view. Microglia in the pineal have, moreover, been shown to affect the morphology and function of rat pinealocytes. Furthermore, in recent studies, Tsai et al. (Tsai and McNulty 1997, 1999; Tsai et al. 2001) have found that the actions of some cytokines (IFN- and IL-1) on pineal function in vitro are mediated by microglia, whereas other inflammatory mediators (e.g., tumor necrosis factor- and transforming growth factor exert their effects directly on pinealocytes. The mechanisms mediating the actions of immunoregulators within and between these cells are, however, unknown.
Concluding remarks
The pineal gland and the immune system appear to be linked by bidirectional communication. Melatonin functions as an immunoregulatory factor in the development and maturation of the immune system and in the progression of the immune response. The immune system, in turn, appears to reciprocally regulate pineal gland function, mainly via cytokines produced by activated immune cells, although the precise mechanism(s) involved are, as yet, largely unknown.
Acknowledgements
This work was supported by grants from the State Committee for Scientific Research (KBN) 6 P04C 04320 and 6 P04C 08921, agreed to the Department of Vertebrate Physiology, Warsaw University. The work of B.O. and R.O. was performed within the Statutory Project No. S.1.2. of the Institute of Genetics and Animal Breeding of Polish Academy of Sciences. R.O. was recipient of a NATO fellowship (Poland).
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