In recent years, melatonin, i.e. the major endocrine product of the pineal gland, was investigated as to its possible regulatory role in the communication between the neuroendocrine and the immune systems. First indications that melatonin may be an endocrine immunomodulator came from early reports about antitumor effects in animals and humans. Since then evidence has accumulated suggesting that melatonin – as a well-preserved molecule during evolution – is indeed involved in the feedback between neuroendocrine and immune functions. At present we begin to discover molecular mechanisms, by which melatonin affects cellular functions in general, and from the variety of possible direct and indirect interactions it appears that melatonin may play a complex physiological role in neuroimmunomodulation. In this article we want to give a critical review of the numerous reports on melatonin influencing immune functions, and to discuss the possible different mechanisms of action, which were suggested recently.

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A BSTRACT : Our work is devoted to defining relationships between the immune system and the adrenergic and cholinergic systems in vivo. In the rat model, we have shown that the cells of different immune compartments express the genes of a defined set of adrenergic/cholinergic receptors, and it was shown that lymphocytes are a site of non-neuronal production of norepinephrine and acetylcholine. Furthermore, using implantable slow-release tablets containing adrenergic or cholinergic agonists/antagonists, distinct and partly opposite effects were observed on peripheral immune functions. Concerning sympathetic immunoregulation, our data-in contrast to those of other studiessuggest that an enhanced adrenergic tonus leads to immunosuppression primarily via ␣ 2 -receptor-mediated mechanisms. Beta-blockade strongly enhances this effect, most likely by inhibition of pineal melatonin synthesis. In recent experiments on the kinetics it was found that the continuous ␣ -adrenergic treatment entails a strong suppression of cellular responsiveness during the first few hours, which is increasingly followed by a general loss of lymphocytes in blood and lymphoid organs most likely due to enhanced apoptosis. More recently, we have extended our studies to the mouse model. First data obtained with RNAse protection assays suggest a biphasic effect on the gene expression of several cytokines in spleen cells due to adrenergic in vivo treatment.

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Unlike splenic or blood lymphocytes, rat thymocytes spontaneously undergo continuously increasing apoptosis during culture. In this study we characterized apoptotic thymus cells of rats according to cell size, nuclear dye binding and surface marker expression. Furthermore, the effects of cell density in culture, the age of the donor animals, giucocorticoids, and inhibition of protein synthesis were studied. It was found that: (1) apoptotic rat thymocytes are recognized in flow cytometry as small, acridine orange^low, CD4^low, CD8^high cells; (2) the rate of apoptosis is dependent on the cell density in the culture in a biphasic manner; (3) thymic apoptosis increases with age of the donor animal in fresh, as well as in 24-hour cultivated cell suspensions; (4) neither adrenalectomy nor in vivo or in vitro treatment with the glucocorticoid antagonist RU 38486 influenced spontaneous apoptosis of thymocytes, and (5) inhibition of protein synthesis, which decreases apoptosis induced by corticosterone, had no effect on spontaneous apoptosis of thymocytes.