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Human Lymphocyte-Synthesized Melatonin Is Involved in the Regulation of the Interleukin-2/Interleukin-2 Receptor System

Departments of Medical Biochemistry and Molecular Biology (A.C.-V., P.J.L., J.R.C., J.M.G.) and Normal and Pathological Cytology and Histology (J.M.F.-S., I.M.-L.), The University of Seville School of Medicine and Virgen Macarena Hospital, 41009 Seville, Spain; and Laboratory of Electron Microscopy (M.K.), Department of Pathology, Medical University of Lodz, 92-216 Lodz, Poland

Address all correspondence and requests for reprints to: Juan M. Guerrero, Department of Medical Biochemistry and Molecular Biology, The University of Seville School of Medicine, Avda. Sánchez Pizjuán 4, 41009 Seville, Spain. E-mail: guerrero{at}us.es.

Since melatonin was first isolated in 1958 up to the last few years, this substance was considered a hormone exclusive to the pineal gland. Although melatonin has lately been identified in a large number of extrapineal sites, its potential biological actions have not yet been studied. This paper shows that human lymphocyte-synthesized melatonin plays a crucial role modulating IL-2/IL-2 receptor system because when blocking melatonin biosynthesis by the tryptophan hydroxylase inhibitor, parachlorophenylalanine, both IL-2 and IL-2 receptor levels fell, restoring them by adding exogenous melatonin. Moreover, we demonstrated that this endogenous melatonin interfered with the exogenous melatonin effect on IL-2 production. Melatonin exerted these effects by a receptor-mediated action mechanism because both IL-2 and IL-2 receptor expressions significantly decreased when lymphocytes were incubated in the presence of the specific membrane and/or nuclear melatonin receptor antagonists, luzindole, and/or CGP 55644, respectively. Finally, we made the real significance of the membrane melatonin receptors in this process clear, so prostaglandin E₂-induced inhibition on IL-2 production increased when we blocked the membrane receptors using luzindole. In conclusion, these data show that endogenous melatonin is an essential part for an accurate response of human lymphocytes through the modulation of IL-2/IL-2 receptor system.

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