The pineal gland is a vertebrate neuroendocrine organ able to transduce the information on external lighting condition into the biochemical message. Rhythmical synthesis and release of its principal hormone, melatonin (MEL), bring about an essential message on both the diurnal and seasonal changes in the external environment. This message may be, in turn, involved in the regulatory network responsible for keeping homeostasis within the vertebrate’s body. It comprises the nervous, endocrine and immune systems, able also to communicate reciprocally and to co-operate, using the same message and receptor molecules. MEL involvement in this network has been recently accepted as its receptors were discovered not only within central nervous system but also in several peripheral tissues. Using different experimental approaches both membrane-bound and nuclear MEL receptors were demonstrated within lymphoid glands and circulating immune cells. In lymphocytes a negative correlation between MEL-regulated cAMP content, via specific G protein-coupled receptors, and lymphocyte proliferation has been shown.

Communication between immune and neuroendocrine systems (including the pineal gland) may be considered on two levels: an antigen-independent strategic one and an antigen-stimulated emergency circuit. The strategic level means that the normal development and function of both parts of this network are reciprocally dependent. In chicken embryo, pinealectomised very early during incubation, a retarded development of the primary lymphoid glands and a decreased immune response accompanied by the significant changes in the biogenic amines concentration in the spleen and brain were demonstrated. Thus development of the immune system seems to remain under regulatory influence of the pineal gland, exerted either directly on the lymphoid organs, and/or indirectly, via the neuroendocrine network. Recently, a parallel pattern of the diurnal rhythms of MEL and thymic hormones was demonstrated in rats and humans. On the other hand, an avian primary lymphoid gland, bursa of Fabricius, influences normal development of the pineal gland function, as the embryonic bursectomy evoked an alleviation of the circadian rhythm of MEL synthesis and this effect was reversed by the treatment with very low doses of bursin, a bursal tripeptide hormone. In laboratory rodents, pinealectomy performed during postnatal life caused an involution of the thymus, associated with a depression of several immune parameters, restored by the evening administration of MEL. Additional support for the strategic level of relationships between MEL and the immune system comes from the demonstration that this hormone was not only present, but also synthesized within lymphoid cells and haemopoietic tissue.

The influence of MEL on immune response (emergency level) was examined in various experimental approaches, but the results are still controversial. The effects observed strongly depended on the experimental model, including species, sex and age of the animal examined, method and extent of immune system activation, immune parameter examined, MEL dose and duration of treatment, as well as on factors not frequently taken into consideration, such as the circadian rhythm (both the pineal gland and immune system function), season, stressing conditions, etc. MEL has been shown to modulate several immune functions, such as antibody production, lymphocyte proliferation, ADCC activity, NK cell cytotoxicity, cytokine synthesis and release, inflammatory reaction, etc. Taking into consideration a versatility of MEL function, its facility to penetrate cells as well as the binding sites present in the cell membrane and the nucleus, one can assume numerous mechanisms involved in its regulatory activity. Among them, a mediation of the endogenous opioids and/or various cytokines as well as free radical scavenging were postulated.

To close a regulatory loop between the immune system and the pineal gland it is absolutely necessary that the messages sent by the activated immune system are understood by the pineal gland, i.e. the activation of the immune system influenced the pineal gland activity and, therefore, peripheral MEL level. The effects exerted by the immune system activated in different way (cytokine injection, immunisation with non-pathogenic antigen, inflammatory reaction) clearly indicated that both circadian rhythm of the pineal gland activity and serum MEL concentration varied in these conditions. Therefore, one can assume that the biochemical message sent by the pineal gland may be adjusted not only to the external lighting conditions but also to the actual performance of the immune system.