Abstract
Daily oscillation of the immune system follows the central biological clock outputs control such as melatonin produced by the pineal gland. Despite the literature showing that melatonin is also synthesized by macrophages and T lymphocytes, no information is available regarding the temporal profile of the melatonergic system of immune cells and organs in steady-state. Here, the expression of the enzymes arylalkylamine-N-acetyltransferase (AA-NAT), its phosphorylated form (P-AA-NAT) and acetylserotonin-O-methyltransferase (ASMT) were evaluated in phagocytes and T cells of the bone marrow (BM) and spleen. We also determined how the melatonergic system of these cells is modulated by LPS and the cytokine IL-10. The expression of the melatonergic enzymes showed daily rhythms in BM and spleen cells. Melatonin rhythm in the BM, but not in the spleen, follows P-AA-NAT daily variation. In BM cells, LPS and IL10 induced an increase in melatonin levels associated with the increased expressions of P-AA-NAT and ASMT. In spleen cells, LPS induced an increase in the expression of P-AA-NAT but not of melatonin. Conversely, IL10 induced a significant increase in melatonin production associated with increased AA-NAT/P-AA-NAT expressions. In conclusion, BM and spleen cells present different profiles of circadian production of local melatonin and responses to immune signals.
Highlights
In order to evaluate whether the bone marrow (BM) and the spleen could synthesize melatonin, we determined the expression of the enzymes AA-NAT, its active form (P-AA-NAT), and ASMT
The mean fluorescence intensity (MFI) of AA-NAT and P-AA-NAT had non-circadian rhythms, but the MFI of P-AA-NAT peaked at ZT18
Previous studies have shown the presence of the melatonergic biosynthetic pathway enzymes (AA-NAT/P-AA-NAT and ASMT) in extra-pineal tissues and the existence of extra-pineal melatonin synthesis
Summary
The expression of the melatonergic enzymes showed daily rhythms in BM and spleen cells. Melatonin rhythm in the BM, but not in the spleen, follows P-AA-NAT daily variation. In BM cells, LPS and IL10 induced an increase in melatonin levels associated with the increased expressions of P-AA-NAT and ASMT. The intrinsic circadian clock of most of the immune cells imposes circadian expression of downstream genes and functions[4]. This is the case for the expression of pattern-recognition receptors and cytokines, the recruitment to tissues and the phagocytic activity of monocytes, macrophages and microglia[7,8,9,10]. The darkness hormone melatonin, prolactin and glucocorticoids impose, for example, a daily rhythm in the migration of leukocytes to peripheral tissues[6]
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