Nonclassic Actions of Vitamin D

doi:10.1210/JC.2008-1454

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Nonclassic Actions of Vitamin D

Journal Article•DOI•

Nonclassic Actions of Vitamin D

Daniel D. Bikle¹•Institutions (1)

Veterans Health Administration¹

01 Jan 2009-The Journal of Clinical Endocrinology and Metabolism (The Endocrine Society)-Vol. 94, Iss: 1, pp 26-34

TL;DR: The nonclassic actions of vitamin D are cell specific and provide a number of potential new clinical applications for 1,25(OH)(2)D(3) and its analogs, however, the use ofitamin D metabolites and analogs for these applications remains limited by the classic actions of Vitamin D leading to hypercalcemia and hypercalcuria.

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Abstract: Context: Vitamin D receptors are found in most tissues, not just those participating in the classic actions of vitamin D such as bone, gut, and kidney. These nonclassic tissues are therefore potential targets for the active metabolite of vitamin D, 1,25(OH)2D. Furthermore, many of these tissues also contain the enzyme CYP27B1 capable of producing 1,25(OH)2D from the circulating form of vitamin D. This review was intended to highlight the actions of 1,25(OH)2D in several of these tissues but starts with a review of vitamin D production, metabolism, and molecular mechanism. Evidence Acquisition: Medline was searched for articles describing actions of 1,25(OH)2D on parathyroid hormone and insulin secretion, immune responses, keratinocytes, and cancer. Evidence Synthesis: Vitamin D production in the skin provides an efficient source of vitamin D. Subsequent metabolism to 1,25(OH)2D within nonrenal tissues differs from that in the kidney. Although vitamin D receptor mediates the actions of 1,25(OH)2D, regulati...

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Journal Article•DOI•

Vitamin D deficiency.

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T E Oppé

21 Jul 1979-BMJ

TL;DR: It is suggested that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units, outpatients, and referrals to social services, but for house doctors to assess overdoses would provide no economy for the psychiatric or social services.

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Abstract: admission. This proportion could already be greater in some parts of the country and may increase if referrals of cases of self-poisoning increase faster than the facilities for their assessment and management. The provision of social work and psychiatric expertise in casualty departments may be one means of preventing unnecessary medical admissions without risk to the patients. Dr Blake's and Dr Bramble's figures do not demonstrate, however, that any advantage would attach to medical teams taking over assessment from psychiatrists except that, by implication, assessments would be completed sooner by staff working on the ward full time. What the figures actually suggest is that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units (by 19°U), outpatients (by 5O°'), and referrals to social services (by 140o). So for house doctors to assess overdoses would provide no economy for the psychiatric or social services. The study does not tell us what the consequences would have been for the six patients who the psychiatrists would have admitted but to whom the house doctors would have offered outpatient appointments. E J SALTER

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4,497 citations

Journal Article•DOI•

Vitamin D: modulator of the immune system.

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Femke Baeke¹, Tatiana Takiishi¹, Hannelie Korf¹, Conny Gysemans¹, Chantal Mathieu¹ - Show less +1 more•Institutions (1)

Katholieke Universiteit Leuven¹

01 Aug 2010-Current Opinion in Pharmacology

TL;DR: 1,25(OH)(2)D(3) is described as an immunomodulator targeting various immune cells, including monocytes, macrophages, dendritic cells (DCs), as well as T-lymphocytes and B-LYmphocytes, hence modulating both innate and adaptive immune responses.

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1,076 citations

Cites background from "Nonclassic Actions of Vitamin D"

...Indeed, activation of these VDRs has so-called nonclassical effects, which include the modulation of growth, differentiation status, and function of a variety of cells, exposing additional roles for vitamin D in the regulation of immune responses, cardiovascular processes, and in cancer prevention [1 ,2]....
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...Of interest, VDRs are not only present in different tissues (Figure 2), such as bone, skin, intestine, and kidneys but also non-classical organs like brain, eyes, heart, pancreatic islets (b-cells), immune cells, muscle, adipose tissue, thyroid, parathyroid, and adrenal glands (reviewed in [1])....
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Journal Article•DOI•

Vitamin D and the immune system.

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Cynthia Aranow¹•Institutions (1)

The Feinstein Institute for Medical Research¹

01 Aug 2011-Journal of Investigative Medicine

TL;DR: As immune cells in autoimmune diseases are responsive to the ameliorative effects of vitamin D, the beneficial effects of supplementing vitamin D-deficient individuals with autoimmune disease may extend beyond the effects on bone and calcium homeostasis.

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Abstract: It is now clear that vitamin D has important roles in addition to its classic effects on calcium and bone homeostasis. As the vitamin D receptor is expressed on immune cells (B cells, T cells, and antigen-presenting cells), and these immunologic cells are all capable of synthesizing the active vitamin D metabolite, vitamin D has the capability of acting in an autocrine manner in a local immunologic milieu. Vitamin D can modulate the innate and adaptive immune responses. Deficiency in vitamin D is associated with increased autoimmunity and an increased susceptibility to infection. As immune cells in autoimmune diseases are responsive to the ameliorative effects of vitamin D, the beneficial effects of supplementing vitamin D-deficient individuals with autoimmune disease may extend beyond the effects on bone and calcium homeostasis.

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774 citations

Cites background from "Nonclassic Actions of Vitamin D"

...Many tissues other than the skeletal and intestine express the VDR including cells in the bone marrow, brain, colon, breast, malignant cells, and immune cells suggesting that vitamin D may have functions other than calcium and bone homeostasis.(2) Additionally, tissues other than the kidney express 1->-hydroxylase and are capable of converting 25 D to 1,25 D, in nonrenal compartments....
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Journal Article•DOI•

Mechanisms of the Anti-Cancer and Anti-Inflammatory Actions of Vitamin D

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Aruna V. Krishnan¹, David Feldman¹•Institutions (1)

Stanford University¹

06 Jan 2011-Annual Review of Pharmacology and Toxicology

TL;DR: Calcitriol exerts multiple anti-proliferative, pro-apoptotic, and pro-differentiating actions on various malignant cells and retards tumor growth in animal models of cancer.

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Abstract: Calcitriol, the hormonally active form of vitamin D, is being evaluated in clinical trials as an anti-cancer agent. Calcitriol exerts multiple anti-proliferative, pro-apoptotic, and pro-differentiating actions on various malignant cells and retards tumor growth in animal models of cancer. Calcitriol also exhibits several anti-inflammatory effects including suppression of prostaglandin (PG) action, inhibition of p38 stress kinase signaling, and the subsequent production of pro-inflammatory cytokines and inhibition of NF-κB signaling. Calcitriol also decreases the expression of aromatase, the enzyme that catalyzes estrogen synthesis in breast cancer, both by a direct transcriptional repression and indirectly by reducing PGs, which are major stimulators of aromatase transcription. Other important effects include the suppression of tumor angiogenesis, invasion, and metastasis. These calcitriol actions provide a basis for its potential use in cancer therapy and chemoprevention. We summarize the status of trials involving calcitriol and its analogs, used alone or in combination with known anti-cancer agents.

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414 citations

Cites background from "Nonclassic Actions of Vitamin D"

...Calcitriol inhibits the synthesis and biological actions of pro-inflammatory PGs by three mechanisms: (1) suppression of the expression of cyclooxygenase-2 (COX-2), the enzyme that synthesizes PGs, (2) upregulation of the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the enzyme that inactivates PGs, and (3) downregulation of the expression of PG receptors that are essential for PG signaling....
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...These include (1) the inhibition of prostaglandin (PG) synthesis and biological actions; (2) the induction of MAP kinase phosphatase 5 (MKP5) expression, subsequent inhibition of p38 stress kinase activation, and production of pro-inflammatory cytokines such as interleukin-6 (IL-6); (3) the upregulation of the expression of insulin-like growth factor binding protein-3 (IGFBP-3), which suppresses proliferation and inhibits NF-κB activation; (4) the inhibition of nuclear factor κB (NF-κB) signaling, which results in the attenuation of the synthesis of pro-inflammatory cytokines such as interleukin-8 (IL-8); (5) the inhibition of tumor angiogenesis due to suppressive effects on the expression of pro-angiogenic factors such as hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor (VEGF), and IL-8; and (6) the decrease in the expression of matrix metalloproteinase 9 (MMP-9) and (7) the increase in the expression of E-cadherin, leading to the inhibition of invasion and metastasis....
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Journal Article•DOI•

Modulation of the immune system by UV radiation: more than just the effects of vitamin D?

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Prue H. Hart¹, Shelley Gorman¹, John J. Finlay-Jones¹•Institutions (1)

Telethon Institute for Child Health Research¹

01 Sep 2011-Nature Reviews Immunology

TL;DR: The effects of UV radiation and vitamin D on immune function in immunopathological diseases, such as psoriasis, multiple sclerosis and asthma, and during infection are compared and contrast.

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Abstract: Humans obtain most of their vitamin D through the exposure of skin to sunlight. The immunoregulatory properties of vitamin D have been demonstrated in studies showing that vitamin D deficiency is associated with poor immune function and increased disease susceptibility. The benefits of moderate ultraviolet (UV) radiation exposure and the positive latitude gradients observed for some immune-mediated diseases may therefore reflect the activities of UV-induced vitamin D. Alternatively, other mediators that are induced by UV radiation may be more important for UV-mediated immunomodulation. Here, we compare and contrast the effects of UV radiation and vitamin D on immune function in immunopathological diseases, such as psoriasis, multiple sclerosis and asthma, and during infection.

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401 citations

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References

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Journal Article•

Akufo and ibarapa.

[...]

Beckett Ah, Rowland M, Paul Turner

06 Feb 1965-The Lancet

17,468 citations

Journal Article•DOI•

Vitamin D Deficiency

[...]

Michael F. Holick¹•Institutions (1)

Boston Medical Center¹

19 Jul 2007-The New England Journal of Medicine

TL;DR: The role of vitamin D in skeletal and nonskeletal health is considered and strategies for the prevention and treatment ofitamin D deficiency are suggested.

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Abstract: Once foods in the United States were fortified with vitamin D, rickets appeared to have been conquered, and many considered major health problems from vitamin D deficiency resolved. But vitamin D deficiency is common. This review considers the role of vitamin D in skeletal and nonskeletal health and suggests strategies for the prevention and treatment of vitamin D deficiency.

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11,849 citations

Journal Article•DOI•

Vitamin D deficiency.

[...]

T E Oppé

21 Jul 1979-BMJ

...read moreread less

4,497 citations

"Nonclassic Actions of Vitamin D" refers background in this paper

...25OHD production is primarily substrate dependent, so serum 25OHD is a reliable indicator of vitamin D status (10)....
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Journal Article•DOI•

Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response

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Philip T. Liu¹, Steffen Stenger, Huiying Li, Linda Wenzel, Belinda H. Tan, Stephan R. Krutzik, Maria Teresa Ochoa, Jürgen Schauber, Kent Wu, Christoph Meinken, Diane L. Kamen, Manfred Wagner, Robert Bals, Andreas Steinmeyer, Ulrich Zügel, Richard L. Gallo, David Eisenberg, Martin Hewison, Bruce W. Hollis, John S. Adams, Barry R. Bloom, Robert L. Modlin - Show less +18 more•Institutions (1)

University of California, Los Angeles¹

24 Mar 2006-Science

TL;DR: The data support a link between TLRs and vitamin D–mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection.

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Abstract: In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide. We report here that TLR activation of human macrophages up-regulated expression of the vitamin D receptor and the vitamin D-1-hydroxylase genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis. We also observed that sera from African-American individuals, known to have increased susceptibility to tuberculosis, had low 25-hydroxyvitamin D and were inefficient in supporting cathelicidin messenger RNA induction. These data support a link between TLRs and vitamin D-mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection.

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3,242 citations

"Nonclassic Actions of Vitamin D" refers background in this paper

...In these cells 1,25(OH)2D3 production appears to be governed primarily by theavailabilityof substrate (14)....
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...When macrophages are activated via specific tolllike receptors (TLRs), CYP27B1 is induced (14)....
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...Stimulation of TLR2 by an antimicrobial peptide in macrophages (14) or stimulation of TLR2 in keratinocytesbywoundingtheepidermis (16)results in increasedexpression ofCYP27B1,which inthepresenceofadequatesubstrate (25OHD) stimulates the expression of cathelicidin....
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...Inadequate 25OHD levels fail to support this process (14)....
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...Lack of substrate (25OHD), VDR, or CYP27B1 blunts the ability of these cells to respond to a challenge with respect to cathelicidin production (14, 16, 69)....
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A Systematic Review and Meta-analysis

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Paul S. Chan, Renuka Jain, Brahmajee K. Nallmothu, Robert A. Berg, Comilla Sasson - Show less +1 more

01 Jan 2010

TL;DR: A systematic review of studies published from January 1, 1950, through November 31, 2008 using PubMed, EMBASE, Web of Knowledge, CINAHL, and all Evidence-Based Medicine Reviews found that randomized clinical trials and prospective studies of RRTs that reported data on changes in the primary outcome of hospital mortality or the secondary outcome of cardiopulmonary arrest cases were included.

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Abstract: Methods: We conducted a systematic review of studies published from January 1, 1950, through November 31, 2008, using PubMed, EMBASE, Web of Knowledge, CINAHL, and all Evidence-Based Medicine Reviews. Randomized clinical trials and prospective studies of RRTs that reported data on changes in the primary outcome of hospital mortality or the secondary outcome of cardiopulmonary arrest cases were included.

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2,958 citations