Abstract
Calcitriol, the bioactive form of vitamin D, exerts its biological functions by binding to its cognate receptor VDR. In recent years, large-scale randomized controlled trials have been developed and conducted in response to epidemiological studies that have demonstrated significant associations between vitamin D deficiency and a range of adverse extra-skeletal clinical outcomes. Moreover, indicators of the severity of allergies and asthma have been linked to low vitamin D levels. However, the role of calcitriol in regulating IL-4 and IL-13; two cytokines pivotal to allergic inflammation, remained unclear. Our study observed a decrease in IL-4 and IL-13 secretion in murine and human Th2 cells, treated with calcitriol. In murine Th2 cells, Gata3 expression was attenuated by calcitriol. However, the expression of the transcriptional repressor Gfi1, that prevents Th1 fate of activated CD4+ T cells, too was attenuated in the presence of calcitriol. Ectopic expression of either Gfi1 or VDR impaired the secretion of IL-13 in Th2 cells. Gfi1 significantly impairedIl13promoter activation; which calcitriol failed to restore. Ecr, a conserved region between the two genes, which enhanced the transactivation ofIl4andIl13promoters; is essential for calcitriol-mediated suppression of both the genes. In murine Th2 cells, VDR interacted with Gata3 but not Gfi1. Calcitriol augmented the recruitment of VDR to theIl13promoter and Ecr regions. Gata3 recruitment was significantly impaired atIl13and Ecr locus in the presence of calcitriol but increased atIl4promoter. However, in the presence of calcitriol, the overall recruitment of Gfi1 remained unchanged atIl4but increased atIl13locus in Th2 cells. Together, our study clearly elucidates that calcitriol modulates VDR, Gata3, and Gfi1 to suppress IL-4 and IL-13 production in Th2 cells.Abstract Figure
Publisher
Cold Spring Harbor Laboratory