Regina P. Markus, Ph.D
Professor
Office: Institute of Bioscience, University of São Paulo, Rua do Matão, travessa 14, 101, r.323, São Paulo, 05508-900, Brazil
Tel: +55 11 3091-7612
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Zulma S. Ferreira, Ph.D
Assistant Professor
Office: Institute of Bioscience, University of São Paulo, Rua do Matão, travessa 14, 101, r.323, São Paulo, 05508-900, Brazil
Tel: +55 11 3091-7612
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Pedro Augusto C. M. Fernandes, Ph.D
Assistant Professor
Office: Institute of Bioscience, University of São Paulo, Rua do Matão, travessa 14, 101, r.319, São Paulo, 05508-900, Brazil
Tel: +55 11 3091-0983
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Laboratory of Chronopharmacology
Melatonin is a hormone secreted by the pineal gland in the brain. It forms part of the system that regulates the body’s circadian rhythm. In conditions of darkness, the production of melatonin is stimulated, and ceases again only once it becomes light. However, our recent research has revealed non-pineal sources of melatonin and suggests that this hormone plays a role in other important biological systems.
The Laboratory of Chronopharmacology at the University of São Paulo, Brazil, specializes in the pharmacology of biological rhythms, focusing particularly on melatonin’s role in inflammatory responses. Our lab has developed a novel hypothesis that significantly advances understanding of melatonin’s role in health and disease. After 10 years of intensive research, our team proposed the immune-pineal axis hypothesis in 2007. We have found in early studies that, in humans, mastitis (acute inflammation of the breast) was always accompanied by a reduction in nocturnal melatonin. This initial observation provided the first clues: “The reduction was inversely proportional to the presence of a proinflammatory cytokine that signals through that pathway”. Further, we observed that as soon as the level of the proinflammatory cytokine returned to normal, the nocturnal melatonin surge was re-stablished. Under normal conditions, the pineal gland produces melatonin at night, which inhibits the migration of leukocytes (white blood cells) through endothelial layer. This nocturnal melatonin production should then, be suppressed by infection or danger signals. Indeed, pro-inflammatory cytokines activate receptors on the pineal gland that prevent melatonin synthesis and allow full leukocyte migration. This allows the body to mount an inflammatory response essential for healing. Paradoxically, these very same signals also stimulate the extra-pineal synthesis of melatonin by immunocompetent cells. Through the activation of specialized cells in the brain and the injured tissue, levels of melatonin can reach concentrations almost 10,000 times higher than they do when produced by the pineal gland at night. Thus, a shuttle occurs between the pineal to extrapineal sites for production of melatonin. Thus, melatonin’s function as a marker of darkness becomes a modulator of the innate immune response
“Our theory predicts that the mounting of an inflammatory response depends on suppression of the nocturnal melatonin surge, while melatonin produced by immunocompetent cells is important for the recovery phase in the inflammatory response. Disruptions to the immune-pineal axis could, therefore, lead to permanent suppression of pineal melatonin synthesis and ultimately contribute to disease.”
Funding
São Paulo Research Foundation (FAPESP)
National Council of Research, Technology and Innovation (CNPq)