Melatonin counteracts the inhibitory effect of PGE2 on IL-2 production in human lymphocytes via its mt1 membrane receptor

It is well known that melatonin plays a fundamental role in human neuro-immunomodulation. Thus, melatonin regulates the production of a large number of cytokines, including interleukin-2 (IL-2) in the human system. Both membrane and nuclear receptors for melatonin are present in lymphoid cells. However, most of these effects have been shown to be mediated by the putative nuclear receptor for the neurohormone. In this paper, we show that prostaglandin E-2 (PGE(2)), a potent inflammatory mediator, inhibits IL-2 production in human lymphocytes by a cyclic AMP (cAMP)-dependent mechanism. In this model, melatonin counteracts the effects of PGE(2) on IL-2 and cAMP production. We propose that the effect of melatonin is mediated by a membrane receptor, since similar results were obtained when cells were cultured in the presence of S 20098, a specific melatonin membrane receptor agonist. No effect was observed by using CGP 52608, a nuclear receptor agonist. Moreover, when cells were stimulated with phorbol myristate acetate (PMA), which has been shown to inhibit mt1 melatonin membrane receptor expression, the neurohormone failed to counteract the effect of PGE(2). Therefore, we postulate, for the first time, a physiological role of the mt1 melatonin membrane receptor in the human immune system.