Vitamin D Suppresses Th17 Cytokine Production by Inducing C/EBP Homologous Protein (CHOP) Expression

Abstract

Vitamin D is an essential nutrient that regulates calcium and phosphate transport and bone mineralization (1). In recent years, however, vitamin D has been found to have a much broader range of actions, including regulation of cell differentiation, proliferation, and apoptosis (2). The role of vitamin D in immune system is complex and diverse. The systemic or locally produced active form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25D3), 3 can exercise its effects on several immune cells, including macrophages, dendritic cells, and T and B cells. Several reports indicated that 1,25D3 can act directly on T cells or indirectly on dendritic cells to modulate T cell function (3-6). However, the concentrations of 1,25D3 employed in many studies are often above the physiological range, bringing into question the physiological relevance of the effect of 1,25D3 on T cells. Nonetheless, modulation of CD4ϩ T cells by 1,25D3 is intriguing because several studies have demonstrated that 1,25D3 is capable of suppressing inflammation in vivo (7-10).Recently, a new subset of CD4ϩ T cells, Th17 cells, was reported to have an essential role in dampening local inflammation (11-13). Th17 cells produce proinflammatory molecules, IL-17, IL-17F, and IL-22, which act on tissue resident cells to promote inflammation. TGF␤ and IL-6 are critical in generation of Th17 cells by activating STAT3 and inducing the transcription factors, retinoic acid-related orphan receptor (ROR␥t) (14) and ROR␣ (15). IL-1 and IL-23 are also important cytokines to stabilize and maintain Th17 cells (16,17). Therefore, pathways to regulate Th17 cell development and its cytokines are relevant. Of interest, a previous report indicated that 1,25D3 is able to prevent experimental autoimmune uveitis, partially because of its suppressive effect directly on Th17 cells (10). However, it is not known whether the effect is mediated through vitamin D receptor (VDR) and how 1,25D3 suppresses IL-17 and other Th17 cytokine production in T cells.In this study, we have examined the mechanism whereby 1,25D3 regulates CD4ϩ T cell function at physiological concentrations. We found that in response to 1,25D3, Th17 cells produced reduced levels of cytokines at the protein level, whereas their transcriptions were not affected. Moreover, 1,25D3 treatment in Th17 cells induced the expression of C/EBP homologous protein (CHOP). Overexpression of CHOP in Th17 cells suppressed their cytokine production. Our data thus suggest a post-transcriptional inhibition of Th17 cell function by VDR. EXPERIMENTAL PROCEDURESMice-C57Bl/6-and VDR-deficient mice were purchased from The Jackson Laboratory, and 6 -8-week-old mice were used in experiments. Mice were housed in the specific pathogen-free animal facility at MD Anderson Cancer Center, and the animal experiments were performed using protocols approved by the Institutional Animal Care and Use Committee.Th Cell Differentiation-Naive CD4lo T cells from C57Bl/6 mice were FACS-sorted and stimulated with plate-bound anti-CD3 (0.5 g/ml) plus soluble anti...

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

“…We found no significant enhancing effects of 1,25-(OH) 2 D 3 on CD4 + Foxp3 + Treg cells in Wt or GKO mice, confirming and extending previous data in the EAE model (11,47). Those studies found very low Vdr gene expression in CD4 + Foxp3 + Treg cells, suggesting these cells may be relatively unresponsive to 1,25-(OH) 2 D 3 .…”

“…Vdr transcript abundance was very low in Foxp3-expressing regulatory T cells (Tregs) (11). Because Vdr low-expressing Treg cells are a minority (,1%) of the infiltrating cells and are fewer in GKO mice than Wt mice at EAE stage 3, and most infiltrating cells are Vdr high-expressing Th1 cells, Th17 cells, and macrophages (32,39,46,47), the reduced Vdr expression in GKO mice is unlikely to be explained by the composition of the cellular infiltrate.…”

Role of Vitamin D in Atherosclerosis

“…86 Actually, the IL-17A-dependent response was found to occur in parallel with the Th1-dominant and unfavorable immune response during the atherogenic process. Treatment of T cells in vitro with 1a,25(OH) 2 D 3 suppressed the development of Th17 and inhibited IL-17 production via a posttranscriptional mechanism 87 ( Figure 1). 90 Moreover, 1a,25(OH) 2 D 3 acting as a natural endoplasmic reticulum stress reliever was found to induce an M1 antiatherogenic macrophage/monocyte phenotype over M2 (with increased cholesterol uptake and deposition) and to decrease mRNA expression of the monocyte adhesion molecules PSGL-1, β(1)-integrin, and β(2)-integrin, resulting in an increase of monocyte adhesion to activated endothelium.…”

Microbial Reprogramming Inhibits Western Diet-Associated Obesity

“…Diverse disorders such as asthma and autoimmune diseases associated with Westernized living are widely believed to result from insufficient levels of IL-10 and insufficient immune calibration essential for sustained systemic health [60]. Westernized diets are also low in vitamin D, a nutrient that normally works together with IL-10 to enforce immune tolerance and protect against inflammatory disorders [61][62][63] and some types of cancer [64].…”