Invited Speaker

Melatonin as Intracrine, Autocrine, and Paracrine Agent in Immune System: Its Role in Autoimmune Diseases
Juan M. Guerrero
Spain

Melatonin has been identified in a wide range of organisms from bacteria to human beings. Its biosynthesis from tryptophan involves four well-defined intracellular steps catalyzed by tryptophan hydroxylase, aromatic amino acid decarboxylase, serotonin-N-acetyltransferase, and hydroxyndole-O-methyltransferase.

Here, we document that both resting and phytohemagglutinin-stimulated human lymphocytes synthesize and release large amounts of melatonin. Moreover, we show that the necessary machinery to synthesize melatonin is present in human lymphocytes. Furthermore, melatonin released to the culture medium is synthesized in the cells, because blocking the enzymes required for its biosynthesis or inhibiting protein synthesis in general produced a significant reduction in melatonin release.

Moreover, this inhibition caused a decrease in IL-2 production, which was restored by adding exogenous melatonin. These findings indicate that in addition to pineal gland, human lymphoid cells are an important physiological source of melatonin and that this melatonin could be involved in the regulation of the human immune system, possibly by acting as an intracrine, autocrine, and/or paracrine substance. In this model, the relevance of specific melatonin membrane receptors has been well established and we and other authors have suggested the retinoid-related orphan receptor α (RORα) as a mediator of nuclear melatonin signalling by using pharmacological approaches. However, a melatonin-mediated downstream effect cannot be ruled out and further evidence is needed to support a direct interaction between melatonin and RORα. Here, we show that RORα is not only mainly located in the nucleus of human Jurkat T cells but it is also co-immunoprecipated with melatonin.

Moreover, co-localization studies confirmed the direct interaction between melatonin and RORα in the perinuclear region. After different incubation time points with melatonin, a decrease in nuclear RORα levels was observed, suggesting an inhibitory role of melatonin on RORα transcriptional activity. Interestingly, RORα acts as a molecular switch implicated in the mutually exclusive generation of Th 17 and regulatory T cells, key T cell lineages involved in the harm/protection balance of several immune conditions such as autoimmunity or acute transplant rejection. Therefore, the description of melatonin as a natural ligand of RORα gains a major relevance in immune regulation. We also include new data concerning the synthesis of melatonin by human lymphocytes from autoimmune diseases such as systemic lupus erythematosus, showing that in this autoimmune disease there is an impairment of melatonin production.