Vitamin D Deficiency Suppresses Cell-Mediated Immunity in Vivo

Yang, Shouli; Smith, Craig V.; Prahl, Jean M.; Luo, Xiaolong; DeLuca, Hector F.

doi:10.1006/abbi.1993.1260

Cited by 135 publications

(70 citation statements)

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“…59 Furthermore, calcitriol controls the growth of melanoma cells, [60][61][62] inhibits tumor promotion 63 and angiogenesis, 64 and boosts the immune system. [65][66][67] Recently, the importance of vitamin D in T cell activation has been revealed; they cannot kill virally infected cells or cancer cells unless they have enough vitamin D. 65 Other than our data suggesting low vitamin D 3 levels as one of 2 major risk factors for getting CMM, we believe the other major risk factor is HPV infection. Although we do not present any data to support our belief, we think HPV is involved because HPV-38 is found in over half the CMM biopsies [35][36][37][38] and HPV infection is increasing at an exponential rate in Europe.…”

Section: Discussionmentioning

confidence: 62%

Exponentially increasing incidences of cutaneous malignant melanoma in Europe correlate with low personal annual UV doses and suggests 2 major risk factors

Merrill

Ashrafi

Subramanian

et al. 2015

Dermato-Endocrinology

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(2015) Exponentially increasing incidences of cutaneous malignant melanoma in Europe correlate with low personal annual UV doses and suggests 2 major risk factors, Dermato-Endocrinology, 7:1, e1004018, DOI: 10.1080DOI: 10. /19381980.2014 For several decades the incidence of cutaneous malignant melanoma (CMM) steadily increased in fair-skinned, indoor-working people around the world. Scientists think poor tanning ability resulting in sunburns initiate CMM, but they do not understand why the incidence continues to increase despite the increased use of sunscreens and formulations offering more protection. This paradox, along with lower incidences of CMM in outdoor workers, although they have significantly higher annual UV doses than indoor workers have, perplexes scientists. We found a temporal exponential increase in the CMM incidence indicating second-order reaction kinetics revealing the existence of 2 major risk factors. From epidemiology studies, we know one major risk factor for getting CMM is poor tanning ability and we now propose the other major risk factor may be the Human Papilloma Virus (HPV) because clinicians find b HPVs in over half the biopsies. Moreover, we uncovered yet another paradox; the increasing CMM incidences significantly correlate with decreasing personal annual UV dose, a proxy for low vitamin D 3 levels. We also discovered the incidence of CMM significantly increased with decreasing personal annual UV dose from 1960, when it was almost insignificant, to 2000. UV and other DNA-damaging agents can activate viruses, and UV-induced cytokines can hide HPV from immune surveillance, which may explain why CMM also occurs in anatomical locations where the sun does not shine. Thus, we propose the 2 major risk factors for getting CMM are intermittent UV exposures that result in low cutaneous levels of vitamin D 3 and possibly viral infection.

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Section: Discussionmentioning

confidence: 62%

Exponentially increasing incidences of cutaneous malignant melanoma in Europe correlate with low personal annual UV doses and suggests 2 major risk factors

Merrill

Ashrafi

Subramanian

et al. 2015

Dermato-Endocrinology

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“…Offspring were weaned at 3 weeks of age and fed a purified maintenance diet containing 0. 47% Ca, 0.3% P, 5 ng of 1,25(OH) 2 D 3 (Tetrionics, Madison, WI) per 4 g of diet, and vitamins A, E, and K; the composition of the basal diet is described in Yang et al (37). At 5 weeks of age, the mice were switched to a high-calcium (1.2%) low-phosphorus (0.02%) diet, with supplementary vitamins A, E, D, and K. Egg-white albumin (Teklad, Madison, WI) served as the protein source.…”

Section: Methodsmentioning

confidence: 99%

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D ₃ -1α-hydroxylase promoter activity in the skin

Vanhooke

Prahl

Kimmel-Jehan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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. The second hydroxylation is catalyzed by the 25-hydroxyvitamin D 3 -1␣-hydroxylase (1␣-hydroxylase), a mitochondrial cytochrome P450 enzyme that is the product of the CYP27B1 gene (2-6). Activity of 1␣-hydroxylase is tightly regulated through complex mechanisms that depend on the circulating levels of calcium, phosphorus, parathyroid hormone, and 1,25(OH) 2 D 3 .Mutations in the 1␣-hydroxylase gene are known to cause vitamin D-dependency rickets type I (VDDR-I) (2, 7-9). Patients afflicted with this disease are unable to maintain normal serum calcium and suffer from secondary hyperparathyroidism, rickets, and osteomalacia (10). VDDR-I is cured by administration of physiological doses of 1,25(OH) 2 D 3 (11). Physiological doses of 25-OH-D 3 are noncurative, but high dose administration can be effective (11), presumably due to the ability of 25-OH-D 3 to bind and activate the vitamin D receptor when present in vast excess.The experiments reported by Fraser and Kodicek in 1970 (12) were the first to demonstrate the kidney as the major, if not the only, tissue in which 1,25(OH) 2 D 3 is produced under normal physiological conditions. Over the next several years, extrarenal production of 1,25(OH) 2 D 3 was convincingly demonstrated in pregnant nephrectomized rats and in an anephric patient suffering from sarcoidosis (13-15). In these cases, synthesis was localized to the placenta and the sarcoid macrophages (14,16,17). Production of 1,25(OH) 2 D 3 at other sites has remained a subject of much investigation. A number of research groups have reported 1␣-hydroxylase activity in cultured cells, including those of the skin, bone, cartilage, intestine, prostate, and vascular epithelium (18 -25). Bikle et al. (26) have also reported 1,25(OH) 2 D 3 production in perfused flaps of porcine skin. Local production of 1,25(OH) 2 D 3 has been proposed to regulate cellular function and͞or differentiation in an autocrine or paracrine fashion (18,19,24,27,28), and it has been suggested that keratinocytes could supply 1,25(OH) 2 D 3 to the systemic circulation when renal production of the hormone is impaired (26,29). Production of extrarenal 1,25(OH) 2 D 3 in these experiments is not supported, however, by in vivo metabolic studies in nephrectomized nonpregnant rats. In these studies, two independent research groups were unable to detect 3 H-1,25(OH) 2 D 3 in the tissue or plasma after administering a dose of 3 H-25-OH-D 3 of high specific radioactivity (30,31). These conflicting results demonstrate a need for further investigation of the in vivo expression of the 1␣-hydroxylase. We have approached such an investigation by using gene targeting to replace the 1␣-hydroxylase coding sequence with a bacterial lacZ gene controlled by the 1␣-hydroxylase promoter. The lacZ gene codes for ␤-galactosidase, whose activity is readily detected in situ through histochemical staining with X-Gal (32). Herein we report the successful production of 1␣-hydroxylase null mice harboring the lacZ gene and present our analysis of in vivo 1␣-hydroxylase...

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“…The physiological role of vitamin D in immune responses is not clearly defined. In vivo, both an excess and a deficiency of vitamin D suppress the delayed hypersensitivity response (66) or Ig production (67). Vitamin D-deficient animals and humans have a higher risk of infection, probably related to impaired macrophage function (68).…”

Section: Effects Of 1␣25-(oh) 2 D 3 On Already Differentiated Immatumentioning

confidence: 99%

Vitamin D3 Affects Differentiation, Maturation, and Function of Human Monocyte-Derived Dendritic Cells

Piemonti

Monti

Sironi

et al. 2000

The Journal of Immunology

561

419

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We studied the effects of 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3) on differentiation, maturation, and functions of dendritic cells (DC) differentiated from human monocytes in vitro in the presence of GM-CSF and IL-4 for 7 days. Recovery and morphology were not affected by 1α,25-(OH)2D3 up to 100 nM. DC differentiated in the presence of 10 nM 1α,25-(OH)2D3 (D3-DC) showed a marked decrease in the expression of CD1a, while CD14 remained elevated. Mannose receptor and CD32 were significantly increased, and this correlated with an enhancement of endocytic activity. Costimulatory molecules such as CD40 and CD86 were slightly decreased or nonsignificantly affected (CD80 and MHC II). However, after induction of DC maturation with LPS or incubation with CD40 ligand-transfected cells, D3-DC showed marginal increases in MHC I, MHC II, CD80, CD86, CD40, and CD83. The accessory cell function of D3-DC in classical MLR was also inhibited. Moreover, allogeneic T cells stimulated with D3-DC were poor responders in a second MLR to untreated DC from the same or an unrelated donor, thus indicating the onset of a nonspecific hyporesponsivity. In conclusion, our data suggest that 1α,25-(OH)2D3 may modulate the immune system, acting at the very first step of the immune response through the inhibition of DC differentiation and maturation into potent APC.

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Vitamin D Deficiency Suppresses Cell-Mediated Immunity in Vivo

Cited by 135 publications

References 0 publications

Exponentially increasing incidences of cutaneous malignant melanoma in Europe correlate with low personal annual UV doses and suggests 2 major risk factors

Exponentially increasing incidences of cutaneous malignant melanoma in Europe correlate with low personal annual UV doses and suggests 2 major risk factors

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D ₃ -1α-hydroxylase promoter activity in the skin

Vitamin D3 Affects Differentiation, Maturation, and Function of Human Monocyte-Derived Dendritic Cells

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Vitamin D Deficiency Suppresses Cell-Mediated Immunity in Vivo

Cited by 135 publications

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Exponentially increasing incidences of cutaneous malignant melanoma in Europe correlate with low personal annual UV doses and suggests 2 major risk factors

Exponentially increasing incidences of cutaneous malignant melanoma in Europe correlate with low personal annual UV doses and suggests 2 major risk factors

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D 3 -1α-hydroxylase promoter activity in the skin

Vitamin D3 Affects Differentiation, Maturation, and Function of Human Monocyte-Derived Dendritic Cells

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CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D ₃ -1α-hydroxylase promoter activity in the skin