β-Adrenoceptors Trigger Melatonin Synthesis in Phagocytes

Melatonin (5-methoxy-N-acetylserotonin), the pineal hormone, is also synthesized by immune-competent cells. The pineal hormone signals darkness, while melatonin synthesized on demand by activated macrophages at any hour of the day acts locally, favoring regulatory/tolerant phenotypes. Activation of β-adrenoceptors in pinealocytes is the main route for triggering melatonin synthesis. However, despite the well-known role of β-adrenoceptors in the resolution macrophage phenotype (M2), and the relevance of macrophage synthesized melatonin in facilitating phagocytic activity, there is no information regarding whether activation of β-adrenoceptors would induce melatonin synthesis by monocytes. Here we show that catecholamines stimulate melatonin synthesis in bone marrow-derived dendritic cells and RAW 264.7 macrophages. Activation of β-adrenoceptors promotes the synthesis of melatonin by stimulating cyclic AMP/protein kinase A (PKA) pathway and by activating the nuclear translocation of NF-κB. Considering the great number of macrophages around sympathetic nerve terminals, and the relevance of this system for maintaining macrophages in stages compatible to low-grade inflammation, our data open the possibility that extra-pineal melatonin acts as an autocrine/paracrine signal in macrophages under resolution or tolerant phenotypes.