Melatonin inhibits Th17 differentiation

Abstract

Abstract Hypertension is a leading risk factor for cardiovascular disease, which is a major cause of death worldwide. T cells are required for the development of hypertension. Specifically, we showed that T helper 17 (Th17) cells produce the pro-inflammatory cytokine, IL-17A, which leads to sustained elevations of blood pressure and renal and vascular dysfunction in experimental hypertension. T cell differentiation and trafficking is regulated by circadian clocks. High fat and high salt intake, typical of Western diets, disrupt circadian rhythms and are associated with increased risk for developing cardiovascular disease. These diets are also associated with an increase in Th17 cell differentiation. Melatonin is a major circadian hormone with anti-inflammatory and anti-oxidant actions. To determine the interplay between circadian rhythms and Th17 cell differentiation, we tested the hypothesis that in vitro treatment of Th17 cells with melatonin would inhibit IL-17A cytokine production. Splenic naïve CD4+ T cells from wild type C57Bl/6J male mice were cultured for 72 hours on anti-CD3/anti-CD28 antibody coated plates in the presence or absence of Th17-polarizing cytokines and treated with melatonin (2ng/ml; Sigma Aldrich) or vehicle (0.02% DMSO). IL-17A cytokine levels were analyzed by ELISA. In cells treated with Th17 polarizing cytokines, IL-17A cytokine production was significantly reduced by melatonin. Thus, this study highlights the involvement of circadian control of Th17 cells via the actions of melatonin to suppress Th17 differentiation and IL-17A production. Future studies will determine the effect of melatonin treatment in vivo on development of hypertension and renal/vascular dysfunction.