Hormonal vitamin D upregulates tissue-specific PD-L1 and PD-L2 surface glycoprotein expression in human but not mouse (original) (raw)

Vitamin D Signaling in Inflammation and Cancer: Molecular Mechanisms and Therapeutic Implications

Molecules, 2020

Vitamin D and its active metabolites are important nutrients for human skeletal health. UV irradiation of skin converts 7-dehydrocholesterol into vitamin D3, which metabolized in the liver and kidneys into its active form, 1α,25-dihydroxyvitamin D3. Apart from its classical role in calcium and phosphate regulation, scientists have shown that the vitamin D receptor is expressed in almost all tissues of the body, hence it has numerous biological effects. These includes fetal and adult homeostatic functions in development and differentiation of metabolic, epidermal, endocrine, neurological and immunological systems of the body. Moreover, the expression of vitamin D receptor in the majority of immune cells and the ability of these cells to actively metabolize 25(OH)D3 into its active form 1,25(OH)2D3 reinforces the important role of vitamin D signaling in maintaining a healthy immune system. In addition, several studies have showed that vitamin D has important regulatory roles of mechan...

Human T lymphocytes are direct targets of 1,25-dihydroxyvitamin D3 in the immune system

The Journal of Steroid Biochemistry and Molecular Biology, 2010

Besides its actions on minerals and bone, the bioactive vitamin D metabolite, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), has important immunomodulatory properties. Within the immune system, dendritic cells represent key targets for this hormone and 1,25(OH) 2 D 3 -induced changes in their phenotype and function ultimately affects T lymphocytes. However, the presence of vitamin D receptors (VDR) in activated T cells proposes additional mechanisms for 1,25(OH) 2 D 3 to directly regulate T cell responses. Here, we investigated the expression and kinetics of vitamin D-related genes in human activated T lymphocytes. Different activation stimuli elicited increased VDR-and 1-␣-hydroxylase expression, with a highly similar kinetic pattern. Addition of 1,25(OH) 2 D 3 effectively triggered VDR signaling, as evidenced by 24hydroxylase induction, but only when introduced to T lymphocytes expressing high levels of VDR. This enhanced degree of VDR signaling correlated with a stronger inhibition of cytokines (IFN-␥, IL-10) and modulation of homing receptor expression (CCR10, CLA) in long-term T cell cultures. Importantly, chronic 1,25(OH) 2 D 3 -exposure further amplified VDR signaling and the concomitant T cell modulating effects.

The Vitamin D Receptor and T Cell Function

Frontiers in Immunology, 2013

The vitamin D receptor (VDR) is a nuclear, ligand-dependent transcription factor that in complex with hormonally active vitamin D, 1,25(OH) 2 D 3 , regulates the expression of more than 900 genes involved in a wide array of physiological functions. The impact of 1,25(OH) 2 D 3 -VDR signaling on immune function has been the focus of many recent studies as a link between 1,25(OH) 2 D 3 and susceptibility to various infections and to development of a variety of inflammatory diseases has been suggested. It is also becoming increasingly clear that microbes slow down immune reactivity by dysregulating the VDR ultimately to increase their chance of survival. Immune modulatory therapies that enhance VDR expression and activity are therefore considered in the clinic today to a greater extent. As T cells are of great importance for both protective immunity and development of inflammatory diseases a variety of studies have been engaged investigating the impact of VDR expression in T cells and found that VDR expression and activity plays an important role in both T cell development, differentiation and effector function. In this review we will analyze current knowledge of VDR regulation and function inT cells and discuss its importance for immune activity.

Vitamin D Receptor Modulators for Inflammation and Cancer

Mini-Reviews in Medicinal Chemistry, 2005

1α, 25-dihydroxyvitamin D3 {1,25-(OH) 2 D 3 }, the biologically active form of vitamin D, is an important hormone that is critically required for the maintenance of mineral homeostasis and structural integrity of bones. 1,25-(OH) 2 D 3 accomplishes this by facilitating calcium absorption from the gut and by a direct action on osteoblasts, the bone forming cells. Apart form its classical actions on the gut and bone, 1,25-(OH) 2 D 3 and its synthetic analogs also possess potent anti-proliferative, differentiative and immunomodulatory activities. 1,25-(OH) 2 D 3 exerts these effects through vitamin D receptor (VDR), a ligand-dependent transcription factor that belongs to the superfamily of steroid/thyroid hormone/retinoid nuclear receptors. The presence of VDR in various tissues other than gut and bone, along with their ability to exert differentiation, growth inhibitory and anti-inflammatory action, has set the stage for therapeutic exploitation of VDR ligands for the treatment of various inflammatory indications and cancer. However, the use of VDR ligands in clinic is limited by their major dose-related side effect, namely hypercalcemia/hypercalciuria. Efforts are being undertaken to develop vitamin D receptor modulators (VDRMs) that are tissue-selective and/or gene-selective in their action and these ligands may exhibit increased therapeutic indices. This review explores the recent advances in VDR biology, non-secosteroidal VDR ligands and the current and potential clinical applications of VDR ligands in inflammation and cancer.

Review Mechanisms Underlying the Regulation of Innate and Adaptive Immunity by Vitamin D

2015

Abstract: Non-classical actions of vitamin D were first suggested over 30 years ago when receptors for the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), were detected in various tissues and cells that are not associated with the regulation of calcium homeostasis, including activated human inflammatory cells. The question that remained was the biological significance of the presence of vitamin D receptors in the different tissues and cells and, with regard to the immune system, whether or not vitamin D plays a role in the normal immune response and in modifying immune mediated diseases. In this article findings indicating that vitamin D is a key factor regulating both innate and adaptive immunity are reviewed with a focus on the molecular mechanisms involved. In addition, the physiological significance of vitamin D action, as suggested by in vivo studies in mouse models is discussed. Together, the findings indicate the importance of 1,25(OH)2D3 as a regulator of k...

Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity

Nature Clinical Practice Endocrinology & Metabolism, 2008

Knowledge about the ability of vitamin D to function outside its established role in skeletal homeostasis is not a new phenomenon. Nonclassical immunomodulatory and antiproliferative responses triggered by active 1,25-dihydroxyvitamin D were first reported more than a quarter of a century ago. It is only in recent years, however, that there has been a significant improvement in our understanding of how these nonclassical effects of vitamin D can influence the pathophysiology and possible prevention of human disease. Three particular strands of evidence have been prominent: firstly, population studies have revised our interpretation of normal vitamin D status in humans, suggesting, in turn, that vitamin D insufficiency is a clinical problem of global proportions; secondly, epidemiology has linked vitamin D status with disease susceptibility and/or mortality; and, thirdly, expression of the machinery required to synthesize 1,25-dihydroxyvitamin D in normal human tissue seems to be much more widespread than originally thought. Collectively, these observations suggest that nonclassical metabolism and response to vitamin D might have a significant role in human physiology beyond skeletal and calcium homeostasis. Specific examples of this will be detailed in the current Review, with particular emphasis on the immunomodulatory properties of vitamin D. serum levels of 1,25(OH) 2 D that are frequently observed in patients with granuloma-forming diseases such as sarcoidosis were due to extrarenal expression of the enzyme that activates vitamin D-CP27B (25OHD-1α hydroxylase). 1 In this case, synthesis of 1,25(OH) 2 D from 25OHD was due to expression of CP27B by disease-associated macrophages rather than the classical location of the hydroxylase in proximal tubule cells within the kidney. 2 Consequently, subsequent studies have explored the potential immunomodulatory properties of 1,25(OH) 2 D. 3

Pathway analysis of transcriptomic data shows immunometabolic effects of vitamin D

Journal of molecular endocrinology, 2018

Unbiased genomic screening analyses have highlighted novel immunomodulatory properties of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)D). However, clearer interpretation of the resulting gene expression data is limited by cell model specificity. The aim of the current study was to provide a broader perspective on common gene regulatory pathways associated with innate immune responses to 1,25(OH)D, through systematic re-interrogation of existing gene expression databases from multiple related monocyte models (the THP-1 monocytic cell line (THP-1), monocyte-derived dendritic cells (DCs) and monocytes). Vitamin D receptor (VDR) expression is common to multiple immune cell types, and thus, pathway analysis of gene expression using data from multiple related models provides an inclusive perspective on the immunomodulatory impact of vitamin D. A bioinformatic workflow incorporating pathway analysis using PathVisio and WikiPathways was utilized to compare each set of gen...

Gene Regulation by 1,25-Dihydroxyvitamin D3 in CD4+CD25+ Cells Is Enabled by IL-2

Journal of Investigative Dermatology, 2010

Vitamin D may be responsible for reducing the development and severity of autoimmune and allergic diseases. Topically applied 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) enhances the immunoregulatory ability of CD4 þ CD25 þ T cells residing in the skin-draining lymph nodes (SDLNs) of mice. The mechanisms responsible were investigated by examining the expression of 84 cytokine and cytokine-related genes in a 96-well gene array. CD4 þ CD25 þ cells isolated from the SDLNs of BALB/c mice, 24 and 96 hours after topical treatment with 1,25(OH) 2 D 3 , consistently expressed increased IL-2 mRNA levels and also secreted enhanced quantities of IL-2 after ex vivo stimulation with phorbol 12-myristate 13-acetate and ionomycin. CD4 þ CD25 þ cells from the lymph nodes of naive mice constitutively express the vitamin D receptor, allowing direct modulation by 1,25(OH) 2 D 3 . However, in vitro treatment with 1,25(OH) 2 D 3 did not modify the expression of 84 tested cytokine and cytokine-related mRNAs. It was only in the presence of IL-2 that 1,25(OH) 2 D 3 increased the expression of genes including IL-2 and TLR4. Further, 1,25(OH) 2 D 3 enhanced the ability of IL-2 to stimulate CD4 þ CD25 þ cells to proliferate in vitro and also regulate contact hypersensitivity responses on adoptive transfer into naive mice. Therefore, 1,25(OH) 2 D 3 enabled by IL-2 can directly enhance the regulatory potential of CD4 þ CD25 þ T cells to control immune disease. Abbreviations: 1,25(OH) 2 D 3 , 1,25-dihydroxyvitamin D 3 ; CHS, contact hypersensitivity; SDLN, skin-draining lymph node; VDR, vitamin D receptor Taher YA, van Esch BC, Hofman GA et al. (2008) 1Alpha,25-dihydroxyvitamin D3 potentiates the beneficial effects of allergen immunotherapy in a mouse model of allergic asthma: role for IL-10 and TGF-beta. J Immunol 180:5211-21 Thornton AM, Shevach EM (1998) CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188:287-96 van der Mei IA, Ponsonby AL, Engelson O et al. (2007) The high prevalence of vitamin D insufficiency across Australian populations is only partly explained by season and latitude.

Current Status of Vitamin D Signaling and Its Therapeutic Applications

Vitamin D and in particular its biologically most active metabolite, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), are central endocrine molecules that influence many aspects of human physiology, which are not only the well-known calcium and phosphorus up-take and transport controlling bone formation, but also the control of immune functions and of cellular growth and differentiation. Basically all actions of 1α,25(OH)2D3 are mediated by the transcription factor vitamin D receptor (VDR). The crystal structure of the VDR and detailed knowledge on its molecular interactions with the ligand provide significant insight into the mechanisms of vitamin D signaling. This applies also on the action of the huge number of synthetic 1α,25(OH)2D3 analogues, which have been developed with the goal of a therapeutic application in hyper-proliferative diseases, such as psoriasis, benign prostate hyperplasia and different types of cancer, in immune functions, such as autoimmune diseases and microbial infections, or in bone disorders, such as osteoporosis. Moreover, detailed investigations on many VDR target genes and in particular the recently available genome-wide view on vitamin D signaling allows a more complete view on the potential of the nuclear hormone. In this review we discuss the latest insight into vitamin D signaling in context with the most prominent 1α,25(OH)2D3 analogues.

Molecular Mechanisms of Vitamin D-Mediated Immunomodulation

Galen Medical Journal

Ever since discovering the fat-soluble secosteroid vitamin D, an abundance of research has been conducted on the molecular mechanisms for the multiple health benefits of this nutrient. Studies on the beneficial effects of vitamin D supplementation have found appreciable evidence suggesting that it may play a more prime role than initially presumed. Though it has largely been implicated in bone pathophysiology, novel research on vitamin D indicates its fundamental involvement in a wide range of disease processes through its multiple systemic effects, including but not limited to metabolic, cardiovascular, anti-inflammatory, antineoplastic, antioxidant, neuroprotective, and immune actions. Recent work has yielded important mechanistic insights into the functions of vitamin D in mediating immunity. The present work sheds light on the metabolism and immune response mechanisms of vitamin D. Current review is based on a thorough search of the available relevant research findings of the me...