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bioRxiv · 10.1101/2023.12.03.569823

Calcitriol impairs the secretion of IL-4 and IL-13 in Th2 cells via modulating the transcription factors Gata3 and Gfi1

Biswas, B.·Chattopadhyay, S.·Hazra, S.·Goswami, R.
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Abstract

Calcitriol, the bioactive form of vitamin D, exerts its biological functions by binding to its cognate receptor VDR. The 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 impaired Il13 promoter activation; which calcitriol failed to restore. Ecr, a conserved region between the two genes, which enhanced the transactivation of Il4 and Il13 promoters; 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 the Il13 promoter and Ecr regions. Gata3 recruitment was significantly impaired at Il13 and Ecr locus in the presence of calcitriol but increased at Il4 promoter. However, in the presence of calcitriol, the overall recruitment of Gfi1 remained unchanged at Il4 but increased at Il13 locus 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/569823v3_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1557aaborg.highwire.dtl.DTLVardef@e8b1dcorg.highwire.dtl.DTLVardef@f505dcorg.highwire.dtl.DTLVardef@53b31c_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Biswas, B., Chattopadhyay, S., Hazra, S., Goswami, R.. 2023-12-04. Calcitriol impairs the secretion of IL-4 and IL-13 in Th2 cells via modulating the transcription factors Gata3 and Gfi1. https://doi.org/10.1101/2023.12.03.569823

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