Vitamin D receptor agonists as anti-inflammatory agents

1α,25-dihydroxyvitamin D3 (1,25-[OH]2D3), the biologically active form of vitamin D, is a secosteroid hormone that is essential for bone and mineral homeostasis. In addition, this hormone regulates the growth and differentiation of many cell types and has pronounced immunoregulatory and anti-inflammatory properties. Current therapeutic indications include osteoporosis, secondary hyperparathyroidism and psoriasis, but the anti-proliferative, prodifferentiative, antibacterial, immunomodulatory and anti-inflammatory properties of vitamin D receptor agonists could be exploited in a variety of additional clinical conditions. In particular, the pleiotropic anti-inflammatory effects induced by vitamin D receptor agonists could turn out to be beneficial in different pathologies mediated by chronic inflammatory responses.     

CD4+ T lymphocytes injected into severe combined immunodeficient (SCID) mice lead to an inflammatory and lethal bowel disease

Transfer of 2 × 10⁵ congenic or semiallogenic purified TCRαβ⁺ CD4⁺ T cells to SCID mice leads to an infiltration of the recipient gut lamina propria and epithelium with a donor-derived CD4⁺ T cell subset which induces a lethal inflammatory bowel disease (IBD) in the recipients. In contrast, IBD was not observed in SCID mice transplanted with unfractionated splenic cells. The earliest detectable pathological changes after CD4⁺ T cell transfer were proliferation and hypertrophy of the entire colonic epithelial layer, including increased mitotic activity, increased expression of epithelial nuclear proliferation antigen, and elongation of the crypts. Later on, massive mononuclear cell infiltration, hypertrophy of all layers of the colon and occasional epithelial ulcerations were observed. At this stage, accumulations of IgA, IgM and small numbers of IgG1-, IgG2-and IgG3-secreting plasma cells were present in the lamina propria of both the small and large intestine. We conclude that low numbers of intraveneously transferred CD4⁺ T cells induce IBD in SCID mice. In the late stages of CD4⁺ T cell-induced IBD, the colonic lamina propria becomes infiltrated with macrophages, neutrophils and plasma cells secreting IgA, IgM, and to a lesser degree IgG antibodies which might play an accessory role in the pathogenesis of IBD.     

Vitamin D treatment modulates immune activation in cystic fibrosis

Persistent inflammatory response in cystic fibrosis (CF) airways is believed to play a central role in the progression of lung damage. Anti‐inflammatory treatment may slow lung disease progression, but adverse side effects have limited its use. Vitamin D has immunoregulatory properties. We randomized 16 CF patients to receive vitamin D2, vitamin D3 or to serve as controls, and investigated the effect of vitamin D supplementation on soluble immunological parameters, myeloid dendritic cells (mDCs) and T cell activation. Three months of vitamin D treatment were followed by two washout months. Vitamin D status at baseline was correlated negatively with haptoglobin, erythrocyte sedimentation rate and immunoglobulin A concentration. Total vitamin D dose per kg bodyweight correlated with the down‐modulation of the co‐stimulatory receptor CD86 on mDCs. Vitamin D treatment was associated with reduced CD279 (PD‐1) expression on CD4⁺ and CD8⁺ T cells, as well as decreased frequency of CD8⁺ T cells co‐expressing the activation markers CD38 and human leucocyte antigen D‐related (HLA‐DR) in a dose‐dependent manner. There was a trend towards decreased mucosal‐associated invariant T cells (MAIT) cell frequency in patients receiving vitamin D and free serum 25‐hydroxyvitamin D (free‐s25OHD) correlated positively with CD38 expression by these cells. At the end of intervention, the change in free‐s25OHD was correlated negatively with the change in CD279 (PD‐1) expression on MAIT cells. Collectively, these data indicate that vitamin D has robust pleiotropic immunomodulatory effects in CF. Larger studies are needed to explore the immunomodulatory treatment potential of vitamin D in CF in more detail.     

Vitamin D downregulates the IL-23 receptor pathway in human mucosal group 3 innate lymphoid cells

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Plasma and tissue interleukin-2 receptor levels in inflammatory bowel disease.

Plasma and tissue interleukin-2 receptor (IL-2R) levels were determined in patients with active ulcerative colitis and Crohn's disease. Compared with healthy controls (median 440 U/ml; range 240-900), significantly higher levels of plasma IL-2R were present in patients with active ulcerative colitis (median 1180 U/ml; range 580-7150; P less than 0.002) and Crohn's disease (median 1340 U/ml; range 480-9000; P less than 0.002). Compared with other laboratory parameters, plasma IL-2R levels were related most closely to clinical score of disease activity in Crohn's disease. Plasma IL-2R levels also reflected the clinical course and may provide a more accurate assessment of disease activity in Crohn's disease. In plasma of patients undergoing intestinal resection of active inflammatory bowel disease, raised levels of IL-2R were present in samples from mesenteric vein (draining inflamed intestine) compared with those from peripheral vein. In tissue homogenates of colonic biopsies, significantly higher levels of IL-2R were present in specimens from colons with active ulcerative colitis compared with healthy controls (median 230.2, range 20.7-581.5 versus 77.9, range 34.2-291.3; P less than 0.02).     

Lactobacillus sakei K17, an inducer of IL-10 expression in antigen-presenting cells,attenuates TNBS-induced colitis in mice

To understand the anti-colitic effects of probiotics that up-regulate interleukin (IL)-10 expression in dendritic cells (DCs) and macrophages, we isolated Lactobacillus sakei K17, which potently induced IL-10 expression in DCs and peritoneal macrophages in vitro, among the lactic acid bacteria strains collected from kimchi and investigated its anti-inflammatory effect in mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Oral administration of K17 (2?×?10⁹ CFU·mouse^?1·day^?1) in mice with TNBS-induced colitis suppressed colon shortening and myeloperoxidase activity, as well as infiltration of CD86^+?cells into the colon. Treatment with K17 also increased TNBS-suppressed expression of tight junction proteins and IL-10, but inhibited activation of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases and expression of tumor necrosis factor α and IL-17. Its effect was comparable with that of sulfasalazine (50?mg/kg), a positive commercial ant-colitic drug. Furthermore, treatment with K17 (1?×?10⁵ CFU/mL) potently inhibited lipopolysaccharide (LPS)-stimulated NF-κB activation in DCs and peritoneal macrophages and restored tight junction protein expression in LPS-stimulated Caco-2 cells. These findings suggest that Lactobacillus sakei K17 may ameliorate colitis by up-regulating the expression of IL-10 and tight junction proteins and inhibiting NF-κB activation.     

Mannose-capped lipoarabinomannan-induced B10 cells decrease severity of dextran sodium sulphate-induced inflammatory bowel disease in mice

Inflammatory bowel disease (IBD) is a chronic, non-specific, inflammatory gastrointestinal disease that mainly consists of Crohn's disease and ulcerative colitis. However, the aetiology and pathogenesis of IBD are still unclear. B10 (IL-10 producing regulatory B) cells, a subset of regulatory B cells, are known to contribute to intestinal homeostasis and the aberrant frequency of B10 cells is associated with IBD. We have recently reported that B10 cells can be induced by ManLAM (mannose-capped lipoarabinomannan), a major cell-wall lipoglycan of M tb (Mycobacterium tuberculosis). In the current study, the ManLAM-induced B10 cells were adoptively transferred into IL(interleukin)-10^−/− mice and the roles of ManLAM-induced B10 cells were investigated in DSS (dextran sodium sulphate)-induced IBD model. ManLAM-induced B10 cells decrease colitis severity in the mice. The B10 cells downregulate Th1 polarization in spleen and MLNs (mesenteric lymph nodes) of DSS-treated mice. These results suggest that IL-10 production by ManLAM-treated B cells contributes to keeping the balance between CD4⁺ T cell subsets and protect mice from DSS-induced IBD.     

Vitamin D: does it help Tregs in active rheumatoid arthritis patients

ABSTRACT

Background

Regulatory T cells

(Tregs) play an important role in the maintenance of immunological tolerance. Tregs deficiency or suppressor functions reduction may be associated with autoimmune diseases development.     

Vitamin D receptor gene as a candidate gene for Parkinson disease

Vitamin D and vitamin D receptor (VDR) have been postulated as environmental and genetic factors in neurodegeneration disorders including multiple sclerosis (MS), Alzheimer disease (AD), and recently Parkinson disease (PD). Given the sparse data on PD, we conducted a two-stage study to evaluate the genetic effects of VDR in PD. In the discovery stage, 30 tagSNPs in VDR were tested for association with risk as a discrete trait and age-at-onset (AAO) as a quantitative trait in 770 Caucasian PD families. In the validation stage, 18 VDR SNPs were tested in an independent Caucasian cohort (267 cases and 267 controls) constructed from a genome-wide association study (GWAS). In the discovery dataset, SNPs in the 5' end of VDR were associated with both risk and AAO with more significant evidence of association with AAO (P= 0.0008-0.02). These 5' SNPs were also associated with AD in another study. In the validation dataset, SNPs in the 3' end of VDR were associated with AAO (P= 0.003) but not risk. The 3' end SNP has been associated with both MS and AD in previous studies. Our findings suggest VDR as a potential susceptibility gene and support an essential role of vitamin D in PD.     

Vitamin D receptor gene polymorphisms and uterine fibroid incidence in Caucasian women

IntroductionUterine fibroids (UFs) are benign tumors which are derived from the smooth muscle cells of the uterus. Recent studies have demonstrated that the development of UFs can be particularly related to vitamin D and its receptor. Vitamin D comprises a group of fat-soluble steroid compounds which exert powerful, pleiotropic effects all over the human body. These actions are mediated by a specific type of receptor – vitamin D receptor (VDR). Recent findings have focused on the possible role of VDR genetic variations in the development of several types of diseases, e.g. autoimmune system diseases, various cancers and infections.Material and methodsThe aim of the study was to evaluate the association between rs731236, rs1544410, and rs2228570 polymorphisms in the VDR (vitamin D receptor) gene and the incidence of UFs in Caucasian women. A total of 197 patients (114 fibroid-positive and 83 controls) were included in this retrospective cohort study. VDR gene polymorphisms rs731236 (TaqI), rs1544410 (BsmI) and rs2228570 (FokI) were determined using TaqMan and Simple Probes.ResultsNo statistically significant differences in the occurrence of selected VDR polymorphisms were observed between UF-positive women and healthy controls.ConclusionsWe found no association between rs731236, rs1544410, and rs2228570 VDR polymorphisms and UF incidence in Caucasian women. Larger sample size and multi-ethnic studies are necessary to investigate the matter further.     

Autophagy and pattern recognition receptors in innate immunity

Summary:  Autophagy is a physiologically and immunologically controlled intracellular homeostatic pathway that sequesters and degrades cytoplasmic targets including macromolecular aggregates, cellular organelles such as mitochondria, and whole microbes or their products. Recent advances show that autophagy plays a role in innate immunity in several ways: (i) direct elimination of intracellular microbes by digestion in autolysosomes, (ii) delivery of cytosolic microbial products to pattern recognition receptors (PRRs) in a process referred to as topological inversion, and (iii) as an anti-microbial effector of Toll-like receptors and other PRR signaling. Autophagy eliminates pathogens in vitro and in vivo but, when aberrant due to mutations, contributes to human inflammatory disorders such as Crohn's disease. In this review, we examine these relationships and propose that autophagy is one of the most ancient innate immune defenses that has possibly evolved at the time of α-protobacteria–pre-eukaryote relationships, leading up to modern eukaryotic cell–mitochondrial symbiosis, and that during the metazoan evolution, additional layers of immunological regulation have been superimposed and integrated with this primordial innate immunity mechanism.     

Glucocorticoid-induced tumour necrosis factor receptor family-related receptor signalling exacerbates hapten-induced colitis by CD4+ T cells

The glucocorticoid-induced tumour necrosis factor receptor family related gene (GITR) has been reported to be expressed on the activated T and CD4(+)CD25(+) regulatory T cells (Treg). Signalling triggered by GITR not only neutralizes the suppressive effect of Treg cells, but also augments activation, proliferation and cytokine production of effector T cells. To test the role of GITR in 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis - a murine model of mucosal inflammation - TNBS-injected Balb/c mice were treated with agonistic anti-GITR monoclonal antibody (mAb). Anti-GITR treatment increased the death rate compared to rat IgG-treated mice. Typically, death occurred within 4 days after the TNBS injection when the mice were treated with anti-GITR. The mice that survived anti-GITR treatment suffered from severe inflammation in their entire intestines. CD4(+) T-depletion protected the mice from colitis; even an anti-GITR effect was not apparent. In contrast, CD8(+) T depletion showed less protective than did CD4(+) T depletion. Stimulation of GITR enhanced the production of proinflammatory cytokines including interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-12. It also enhanced the humoral response such as serum levels of IgG(2b) and IgA, which was completely dependent on CD4(+) T cells. Taken together, this study demonstrated that GITR signalling on CD4(+) T cells is involved in the development and progress of colitis by enhancing both T helper type 1 (Th1) and Th2 type responses.     

Vitamin D receptor BsmI polymorphism and osteoporosis risk in post-menopausal women

Introduction

Many studies have suggested that the vitamin D receptor polymorphism BsmI might be associated with the risk of osteoporosis development in post-menopausal women. However, the results have been inconsistent. The aim of this meta-analysis was to derive a more precise evaluation of the relationship.

Material and methods

Published literature from PubMed, EMBASE and the CNKI database was searched. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of any association.

Results

Ten case-control studies were included with a total of 1,403 osteoporosis cases and 2,144 healthy controls. In the overall analysis, no significant association was found between BsmI polymorphism and osteoporosis risk (BB vs. bb: OR = 0.76, 95% CI = 0.39–1.48; BB vs. Bb: OR = 0.90, 95% CI = 0.71–1.15; dominant model: OR = 1.20, 95% CI = 0.74–1.93; recessive model: OR = 0.83, 95% CI = 0.53–1.30). In the subgroup analysis by ethnicity, the results showed similar result that BsmI polymorphism m had no association with osteoporosis.

Conclusions

Results from the current meta-analysis suggest that vitamin D receptor BsmI polymorphism may not be a risk factor for osteoporosis in post-menopausal women.