Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression.
Vitamin D has been shown to have immunomodulatory function, but the molecular basis for it has not been well understood. In this study, we found that vitamin D receptor expression was induced in a CD4+ effector T cell lineage, Th17 cells, which required the transcription factors, RORα, RORγt, and STAT3. Treatment of mice with an active ligand of vitamin D receptor (VDR), 1,25-dihydroxyvitamin D(3) (1,25D3), ameliorated experimental autoimmune encephalomyelitis, accompanied with reduced IL-17 and IL-17F expression. In vitro, treatment of CD4+ T cells with the physiological doses of 1,25D3 preferentially inhibited cytokine production by Th17 cells, in a VDR-dependent manner, without affecting the expression of transcription factors or surface molecules. Moreover, at these concentrations, cytokine expression was suppressed only at protein but not at mRNA levels. Stimulation of Th17 cells with 1,25D3, in a concentration-dependent manner, induced the expression of C/EBP homologous protein (CHOP), a molecule involved in endoplasmic reticulum stress and translational inhibition. In addition, overexpression of CHOP in developing Th17 cells suppressed their cytokine production. Our results suggest a novel, post-transcriptional mechanism whereby Th17 cytokines are inhibited by VDR, which may underscore future therapeutic usage of vitamin D in treatment of autoimmune diseases.
Chang
Seon Hee
SH
Department of Immunology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77054, USA.
Chung
Yeonseok
Y
Dong
Chen
C
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002117:Calcitriol / Q000378:metabolism; D005786:Gene Expression Regulation; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D019041:L-Selectin / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000096:biosynthesis*; D014807:Vitamin D / Q000378:metabolism*
D022762:CCAAT-Enhancer-Binding Proteins; C497249:DDIT3 protein, human; D018960:Hyaluronan Receptors; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D019041:L-Selectin; D014807:Vitamin D; D051742:Transcription Factor CHOP; D002117:Calcitriol