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Effect of vitamin D on endothelial progenitor cells function

Yoav Hammer, Alissa Soudry, [...], and Eli I. Lev


Endothelial progenitor cells (EPCs) are a population of bone marrow-derived cells, which have an important role in the process of endothelialization and vascular repair following injury.
Impairment of EPCs, which occurs in patients with diabetes, was shown to be related to endothelial dysfunction, coronary artery disease (CAD) and adverse clinical outcomes. Recent evidence has shown that calcitriol, the active hormone of vitamin D, has a favorable impact on the endothelium and cardiovascular system. There is limited data on the effect of vitamin D on EPCs function.


To examine the in vitro effects of Calcitriol on EPCs from healthy subjects and patients with diabetes.


Fifty-one patients with type 2 diabetes (60±11 years, 40% women, HbA1C: 9.1±0.8%) and 23 healthy volunteers were recruited. EPCs were isolated and cultured with and without calcitriol. The capacity of the cells to form colony-forming units (CFUs), their viability (measured by MTT assay), KLF-10 levels and angiogenic markers were evaluated after 1 week of culture.


In diabetic patients, EPC CFUs and cell viability were higher in EPCs exposed to calcitriol vs. EPCs not exposed to calcitriol [EPC CFUs: 1.25 (IQR 1.0–2.0) vs. 0.5 (IQR 0.5–1.9), p < 0.001; MTT:0.62 (IQR 0.44–0.93) vs. 0.52 (IQR 0.31–0.62), p = 0.001]. KLF-10 levels tended to be higher in EPCs exposed to vitamin D, with no differences in angiopoietic markers. In healthy subjects, calcitriol supplementation also resulted in higher cell viability [MTT: 0.23 (IQR 0.11–0.46) vs. 0.19 (0.09–0.39), p = 0.04], but without differences in CFU count or angiopoietic markers.


In patients with diabetes mellitus, in vitro vitamin D supplementation improved EPCs capacity to form colonies and viability. Further studies regarding the mechanisms by which vitamin D exerts its effect are required.


Recent evidence indicates that circulating endothelial progenitor cells (EPCs), a population of bone marrow-derived cells, have an important role in the process of vascular repair, by promoting re-endothelialization following vascular injury [1]. EPCs are primarily identified by the expression of cell-surface antigenic markers, including CD133, CD34 and vascular endothelial growth factor receptor 2 (VEGFR-2), and have the ability to differentiate into mature cells with an endothelial phenotype [2]. Impairment of EPCs is related to endothelial dysfunction [3,4], coronary artery disease [5,6], heart failure [7] and adverse clinical outcome [8,9].

Findings from both experimental models and clinical studies support the hypothesis that the biology of EPCs is strongly related to the pathophysiology of coronary artery disease (CAD). Patients with CAD and CAD risk factors (smoking, diabetes, family history and hypertension) have significantly reduced levels of circulating EPCs compared with healthy individuals. Moreover, EPCs isolated from patients with CAD also revealed an impaired migratory response, which was inversely correlated with the number of risk factors [5]. Nevertheless, other studies have yielded conflicting results regarding the role of EPCs in CAD patients, indicating the need for further studies.



Little is known about the effect of vitamin D on the endothelial system, and specifically on EPCs. Our study shows that in vitro vitamin D supplementation improves functional parameters (such as colony forming capacity and viability) of EPCs in patients with diabetes mellitus and to a lesser extent in healthy subjects.

Previous studies displayed reduced levels of circulating EPCs with attenuated functional properties in patients with diabetes mellitus when compared to non-diabetics, and found that tight glycemic control improved their functional capabilities [12]. However, it is not known by which mechanisms diabetes mellitus affects these cells. Possible mechanisms suggested in previous studies are defective nitric oxide (NO) mediated EPC mobilization (from the bone marrow) and homing to injured vessels or tissues [21,22]; as well as increased apoptosis, impaired NO bioavailability, and reduced cell survival [23,24]. These impairments in EPC levels and functional properties may contribute to endothelial dysfunction, atherosclerotic disease progression, and attenuated wound healing observed in patients with diabetes.

Vitamin D has been thoroughly investigated regarding its beneficial cardiovascular effects, yet evidence is sparse regarding its influence on the endothelial system and EPC’s in particular. Previous studies that addressed this issue implied a possible role of vitamin D in EPC metabolism. Cianciolo et al. demonstrated an increased number of vitamin D receptors (VDR) on EPCs in hemodialysis patients treated with oral/IV vitamin D [25]; Yuen-Fung Yiu et al. demonstrated an inverse relationship between serum vitamin D level and circulating EPCs level in patients with diabetes mellitus [26]. Our study is the first to assess in vitro effects of vitamin D supplementation in patients with diabetes. In contrast to the positive effect on functional parameters of the cells, we did not observe any effects of calcitriol supplementation on EPC angiopoietic markers expression (VE-Cadherin, Tie-2). KLF-10 levels did not differ significantly between EPC's supplemented with in vitro vitamin D compared to those who were not, although EPCs from patients with diabetes who were not treated with oral vitamin D prior to their enrollment displayed a trend towards higher KLF-10 levels.

Several potential mechanisms may explain the effects of vitamin D on 37o C. Firstly, as was suggested in our study, vitamin D may modulate KLF-10 levels, which in turn may stimulate activity of EPCs, an effect that was previously described as a possible stimulator of proangiogenic cells [20]. Secondly, vitamin D may modulate NO metabolism and blunt the effect of advanced glycosylation end products (AGE's) as was previously shown in human umbilical cord endothelial cells [19]. Another possible mechanism might relate to the role of vitamin D in modulation of endothelial proinflammatory transcription factor nuclear factor κB (NFkB) as was previously shown in the study of Jablonski et al. [27].

Regardless of the exact mechanism, the relation between in vitro vitamin D supplementation and the improvement of EPCs functional properties may suggest the pathway by which vitamin D exerts its beneficial effects on the cardiovascular system, possibly by attenuating endothelial dysfunction. The fact that in vitro vitamin D supplementation in our study did not improve angiopoietic cellular markers expression on EPCs (Tie-2, VE-Cadherin) invites further studies regarding the mechanisms by which vitamin D influences EPCs and endothelial cells. The pathway of KLF10 may be modulated by vitamin D, although our study failed to establish this relation with certainty. Further studies are also required to examine the effect of in vivo vitamin D treatment on EPC's and the endothelial system.

Our study has several limitations. First, we lack data regarding serum vitamin D levels at time of enrollment in the "diabetes group" and in the "healthy volunteers group". Second, this study assessed only the in vitro effects of vitamin D on EPCs.

Vitamin D has been thoroughly investigated regarding its beneficial cardiovascular effects, yet evidence is sparse regarding its influence on the endothelial system and EPC’s in particular. Previous studies that addressed this issue implied a possible role of vitamin D in EPC metabolism. Cianciolo et al. demonstrated an increased number of vitamin D receptors (VDR) on EPCs in hemodialysis


In vitro vitamin D supplementation improved EPCs viability and ability to form colonies in patients with type 2 diabetes mellitus, and to a lesser extent in healthy subjects. Further studies regarding the mechanisms by which vitamin D exerts its effect are required.


Effect of vitamin D on endothelial progenitor cells function



Vitamin D intake lowers IL-6 levels in the context of ...
Reporting their results in Cancer Prevention Research, the authors found that vitamin D3 supplementation lowered IL-6 levels compared to placebo, but only among those who lost at least 5% of their baseline weight. Vitamin D is a steroid hormone that plays a significant role in calcium homeostasis and metabolism.

Calcifediol Decreases Interleukin-6 Secretion by Cultured ...
Nov 01, 2019 · Accordingly, we expected an increased level of IL-6 in GDM-d trophoblast culture media, but we observed no difference in baseline IL-6 levels between GDM-d and NG trophoblasts. This result might be partly explained by the number of participants taking vitamin D supplementation.

The Impact of Vitamin D Levels on Inflammatory Status: A ...
Nov 03, 2015 · The active metabolite of vitamin D has an anti-inflammatory effect on the inflammatory profile of monocytes [17, 33, 34], down-regulating the expression and production of several pro-inflammatory cytokines including TNF- α, IL-1β, IL-6, and IL-8 [33, 34].

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Publish Year: 2015
Author: Emily K. Calton, Kevin N. Keane, Philip Newsholme, Mario J. Soares
Vitamin D Decreases Hepcidin and Inflammatory Markers in ...
Mar 06, 2019 · There was no significant decrease in IL-6 concentrations after vitamin D supplementation. Iron levels increased from 21 to 32 µg/dL, but these values did not reach a level …

Author: Hadar Moran-Lev, Tut Galai, Anat Yerushalmy-Feler, Yosef Weisman, Adi Anafy, Varda Deutsch, Michal C...
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Anti-inflammatory effects of vitamin D and resistance ...
Jun 24, 2019 · The present study aimed to investigate the anti-inflammatory effects of vitamin D and resistance training in men with type 2 diabetes mellitus and vitamin D deficiency. This study was a randomized, placebo-controlled, double-blinded clinical trial. Trial registration code: IRCT20190204042621N1 Forty-eight patients with type 2 diabetes aged 40–65 (from a total of 52 …
Author: Ali Dadrass, Khalid Mohamadzadeh Salamat, Kamaladdin Hamidi, Kamal Azizbeigi
Publish Year: 2019


The Anti-Inflammatory Effects of Vitamin D in Tumorigenesis
Sep 13, 2018 · Several reports have shown that vitamin D may influence the regulation of IL-6 synthesis. 25(OH)D pretreatment inhibits both UV- and tumor necrosis factor alpha (TNF-α)-stimulated IL-6 production in normal cells via p38 MAPK inhibition, demonstrating its significant anti-inflammatory effects in cancer cells .
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Author: Wei Liu, Lei Zhang, Hui-Jing Xu, Yan Li, Chuan-Min Hu, Jing-Yan Yang, Mei-Yan Sun
Anti-Inflammatory Effects of Vitamin D on Human Immune ...

Dec 12, 2016 · Vitamin D also promotes anti-inflammatory effects through up-regulation of IL-10 . Therefore, it is likely that vitamin D has a critical role in modulating bacterial-specific inflammatoryresponses. Therefore, it is likely that vitamin D has a critical role in modulating bacterial-specific inflammatory responses.
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Author: Edwin Hoe, Jordan Nathanielsz, Zheng Quan Toh, Leena Spry, Rachel Marimla, Anne Balloch, Kim Mulholl...
Vitamin D Has Surprising Anti-Inflammatory Effects On The ...
Vitamin D can also regulate parts of the body with the job of getting rid of inflammation. And vitamin Dkeeps your pro-inflammatory cells from getting out of control. A large scientific review discovered that there are many, many recent studies showing vitamin D has an anti-inflammatory effect on the body in the past few years.


How vitamin D inhibits inflammation -- ScienceDaily Feb 23, 2012 · Vitamin D has long been known to contribute to bone health by promoting the absorption of calcium. In recent years, much attention has been paid to its possible immune and inflammatory benefits. Vitamin D and the Gut's Intestinal Mucosal Barrier - The ... The cause is a largely unfounded and irrational fear of skin cancer. Often times Vitamin D deficiency shows up in infants because the baby’s mother is Vitamin D deficient and the baby is breastfed ( PubMed #PMC3012634 ). Vitamin D deficiency and insufficiency are increasingly common in western cultures. Vitamin D is a powerful tool in taming autoimmunity and ... Dec 28, 2017 · Vitamin D is a powerful tool in taming autoimmunity and inflammation. Vitamin D deficiency is commonly associated with autoimmune conditions such as Hashimoto’s hypothyroidism and type 1 diabetes, as well as muscle pain, neurodegenerative disorders, osteoporosis, impaired wound healing, depression, constant fatigue, and more.


J Immunol. Author manuscript; available in PMC 2009 Nov 15.

Respiratory Epithelial Cells Convert Inactive Vitamin D to its Active Form

Potential Effects on Host Defense1
Sif Hansdottir,*,2 Martha M. Monick,* Sara L. Hinde,* Nina Lovan,* Dwight C. Look,* and Gary W. Hunninghake*
*Department of Medicine, University of Iowa Carver College of Medicine and Veterans Administration Medical Center, Iowa City, IA 52242

The role of vitamin D in innate immunity is increasingly recognized.

Recent work has identified a number of tissues that express the enzyme 1α-hydroxylase and are able to activate vitamin D. This locally produced vitamin D is believed to have important immunomodulatory effects.

In this paper we show that primary lung epithelial cells express high baseline levels of activating 1α-hydroxylase and low levels of inactivating 24-hydroxylase. The result of this enzyme expression is that airway epithelial cells constitutively convert inactive 25-dihydroxyvitamin D3 to the active 1,25-dihydroxyvitamin D3. Active vitamin D that is generated by lung epithelium leads to increased expression of vitamin D regulated genes with important innate immune functions. These include the cathelicidin antimicrobial peptide gene and the TLR co-receptor CD14. Double stranded RNA increases the expression of 1α-hydroxylase, augments the production of active vitamin D, and synergizes with vitamin D to increase expression of cathelicidin. In contrast to induction of the anti-microbial peptide, vitamin D attenuates dsRNA induced expression of the NF-κB driven gene IL-8.

We conclude that primary epithelial cells generate active vitamin D, which then influences the expression of vitamin D driven genes that play a major role in host defense. Furthermore the presence of vitamin D alters induction of antimicrobial peptides and inflammatory cytokines in response to viruses. These observations suggest a novel mechanism by which local conversion of inactive to active vitamin D alters immune function in the lung.





Keywords: Human, Lung, Gene Regulation, Viral, Inflammation

Respiratory Epithelial Cells Convert Inactive Vitamin D to its Active Form


Ethn Dis. Author manuscript; available in PMC 2010 May 31.

Vitamin D and Chronic Kidney Disease
Sandra Williams, MD, Karla Malatesta, BS, and Keith Norris, MD
Charles Drew University of Medicine and Science (SW, KM, KN) and the Geffen School of Medicine, UCLA (KN), Los Angeles, California

Chronic kidney disease (CKD) is an emerging public health problem and one of the most powerful predictors of premature cardiovascular disease. Emerging evidence suggests that the progression of CKD and many of the cardiovascular complications may be linked to hypovitaminosis D. Patients with CKD have an exceptionally high rate of severe vitamin D deficiency that is further exacerbated by the reduced ability to convert 25-(OH)vitamin D into the active form, 1,25 dihydroxy-vitamin D.

As new evidence has improved our understanding of classical, as well as the non-classical, functions for vitamin D, it has become apparent that the autocrine role of vitamin D is an important modulator of several systems including the immune, renal and cardiovascular systems.

In addition to the traditional supplementation of 1,25-vitamin D to CKD patients, by assessing and repleting 25-(OH)vitamin D deficiency, physicians will adequately fuel both the renal and extra-renal pathways of calcitriol synthesis maintaining the classical, as well as the non-classical, functions of vitamin D that ultimately influence clinical outcomes in this high-risk group of patients.

Because of the high rates of hypovitaminosis D and progression of CKD to end-stage renal disease in minority populations, these findings are highly relevant to the national efforts to reduce health disparities. Healthcare providers are called to join the intensified efforts of public health officials to disseminate and implement updated guidelines and recommendations to halt the growing epidemic of vitamin D deficiency, particularly in high-risk populations.


Sandra Williams,医学博士,Karla Malatesta, BS,和Keith Norris,医学博士



慢性肾脏疾病(CKD)是一种新兴的公共卫生问题,也是过早心血管疾病最有力的预测因素之一。新出现的证据表明,慢性肾病的进展,许多心血管并发症可能与维生素缺乏D有关。 CKD患者有异常高的加速的严重缺乏维生素D的能力,降低的25 - (OH)维生素D转化为活性形式1,25 dihydroxy-vitamin D的能力使情况进一步加剧。


除了传统的补充,25-vitamin D CKD患者,通过评估和充满25 (OH)缺乏维生素D,医生将充分促进肾和肾的骨化三醇合成途径维护传统,以及非经典的、功能的维生素D,最终影响这个高危组患者的临床结果。


Keywords: Vitamin D, Chronic Kidney Disease, Cardiovascular

Vitamin D and Chronic Kidney Disease


Biochim Biophys Acta. 2011 Jan;1814(1):186-99. doi: 10.1016/j.bbapap.2010.06.022. Epub 2010 Jul 7.
Cytochromes P450 are essential players in the vitamin D signaling system.

Schuster I1.
Author information
Department of Theoretical Chemistry, University of Vienna, Währingerstraße 17, A 1090 Wien, Austria.

From earliest development on, the vitamin D receptor (VDR) is expressed in most cells of the mammalian body. The VDR is a nuclear, ligand-induced transcription factor that regulates in complex with hormonally active vitamin D the expression of more than 900 genes involved in a wide array of physiological functions (e.g. calcium homeostasis, growth control, differentiation, cognition, immune response, etc.).

Accordingly, severe health problems are associated to vitamin deficiencies. Synthesis of the major active form 1α,25(OH)₂D₃ from vitamin D and subsequent metabolism are exclusively controlled by specific P450-forms. Synthesis, a two-step process, starts with a 25-hydroxylation primarily by CYP2R1 (CYP27A1, CYP2J2, and CYP3A4 may also contribute) and a subsequent 1α-hydroxylation via CYP27B1. Circulating in the bloodstream, 1α,25(OH)₂D₃ acts at sites of VDR expression (target sites) in an endocrine way.

However, it is also capable of autocrine/paracrine functions since various target tissues are fully competent in 1α,25(OH)₂D₃ synthesis, as illustrated by three examples. 1α,25(OH)₂D₃ levels are short-lived: the hormone upregulates its rapid metabolism by CYP24A1 that attacks repeatedly the vitamin D C₂₀₋₂₇ side chain, thereby producing a complex cascade of transient metabolites with increasing polarity.

Most of these metabolites still retain 1α,25(OH)₂D₃-like activities on the VDR, contributing to the overall effect that is commonly attributed to 1α,25(OH)₂D₃. As selective inhibitors of CYP24A1 increase the lifetime and thereby the function of vitamin D metabolites, they will help exploring whether and which intrinsic activities distinct metabolites possess. It appears likely that this strategy may unmask important regulators of new functions.

Copyright © 2010 Elsevier B.V. All rights reserved.

PMID: 20619365 DOI: 10.1016/j.bbapap.2010.06.022

Cytochromes P450 are essential players in the vitamin D signaling system. - PubMed - NCBI


Lab Invest. 2014 Jun;94(6):608-22. doi: 10.1038/labinvest.2014.57. Epub 2014 Apr 14.
Role of local bioactivation of vitamin D by CYP27A1 and CYP2R1 in the control of cell growth in normal endometrium and endometrial carcinoma.

Bergadà L1, Pallares J1, Maria Vittoria A2, Cardus A2, Santacana M1, Valls J3, Cao G4, Fernàndez E2, Dolcet X1, Dusso AS2, Matias-Guiu X1.
Author information
Pathology Group, Pathology and Molecular Genetics Department, Hospital Universitari Arnau de Vilanova, University of Lleida, and IRB-Lleida (Lleida Institute for Biomedical Research), Lleida, Spain.
Division of Nephrology, Hospital Universitari Arnau de Vilanova, University of Lleida, and Experimental Nephrology Department, IRB-Lleida, Lleida, Spain.
Biostatistics Unit, Hospital Universitari Arnau de Vilanova, University of Lleida, and IRB-Lleida, Lleida, Spain.
Laboratory of Clinical Biochemistry, Hospital Universitari Arnau de Vilanova, University of Lleida, and IRB-Lleida, Lleida, Spain.

Vitamin D (VD) deficiency has been suggested as a risk factor for cancer. One recognized mechanism is that the low-serum 25-hydroxyvitamin D (25(OH)D) of VD deficiency reduces intratumoral 25(OH)D conversion to 1α,25-dihydroxyvitamin D (1,25D, the hormonal form of VD), compromising 1,25D-VD receptor (VDR) antitumoral actions.

Reduced tumoral VDR and increased CYP24A1, the enzyme that degrades 1,25D and 25(OH)D, further worsen cancer progression. Importantly, in cells expressing CYP27A1 and/or CYP2R1, which convert inert VD into 25(OH)D, low-serum VD may reduce intratumoral 25(OH)D synthesis thereby compromising VDR antitumoral actions because 25(OH)D can activate the VDR directly and enhance 1,25D-VDR action.

Therefore, this study examined whether abnormal endometrial expression of CYP27A1 and/or CYP2R1 may impair VDR-antiproliferative properties in endometrial carcinoma (EC). Immunohistochemical analysis of tissue microarrays of normal human endometrium (NE; n=60) and EC (n=157) showed the expected lower VDR expression in EC (P=0.0002). Instead, CYP24A1 expression was lower in EC compared with NE, while CYP27A1 and CYP2R1 expressions were higher (P=0.0002; P=0.03). Furthermore, in NE and EC, CYP2R1 and CYP27A1 expression correlated directly with nuclear VDR levels, an indicator of ligand-induced VDR activation, and inversely with the proliferation marker Ki67. Accordingly, in the endometrioid carcinoma cell lines IK, RL95/2 and HEC1-A, which express VDR, CYP27A1, and CYP2R1, VD efficaciously reduced cell viability and colony number, with a time course that paralleled actual increases in both intracellular 25(OH)D and nuclear VDR levels.

Thus, VD may protect from EC progression in part through increased intratumoral 25(OH)D production by CYP27A1 and CYP2R1 for autocrine/paracrine enhancement of 1,25D-VDR-antiproliferative actions.

PMID: 24732451 DOI: 10.1038/labinvest.2014.57




维生素D (VD)缺乏被认为是癌症的一个危险因素。公认的机制之一是人体内25 -羟维生素D 的血清水平low-serum (25 (OH) D) VD缺乏降低瘤内25 (OH) D转换1α,25-dihydroxyvitamin D (1,25 D VD的荷尔蒙的形式),危及1,25 d-vd受体(VDR)抗肿瘤作用。


因此,本研究检测了子宫内膜异常表达CYP27A1和/或CYP2R1是否可能损害子宫内膜癌(EC)的vdr -抗增殖特性。人正常子宫内膜组织微阵列的免疫组化分析(NE;n=60)和EC (n=157)的VDR表达均低于EC (P=0.0002)。相反,与NE相比,EC中CYP24A1的表达较低,而CYP27A1和CYP2R1的表达较高(P=0.0002;P = 0.03)。此外,在NE和EC中,CYP2R1和CYP27A1的表达与配体诱导的VDR激活指标核VDR水平直接相关,与增殖标志物Ki67呈负相关。因此,在表达VDR、CYP27A1和CYP2R1的子宫内膜样癌细胞系IK、RL95/2和HEC1-A中,VD有效地降低了细胞活力和菌落数量,其时间进程与细胞内25(OH)D和核VDR水平的实际增加相一致。

因此,VD可能通过增加CYP27A1和CYP2R1的瘤内25(OH)D的产生来保护EC的进展,从而增强自分泌/旁分泌1,25D- vdr -的抗增殖作用。

Role of local bioactivation of vitamin D by CYP27A1 and CYP2R1 in the control of cell growth in normal endometrium and endometrial carcinoma. - PubMed - NCBI


Oncology. 2012;83(5):264-72. Epub 2012 Sep 5.
Gene expression of vitamin D metabolic enzymes at baseline and in response to vitamin D treatment in thyroid cancer cell lines.

Bennett RG1, Wakeley SE, Hamel FG, High RR, Korch C, Goldner WS.
Author information
Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198-4120, USA.

The association between vitamin D and thyroid cancer is unclear. It is unknown if CYP27A1 or CYP2R1 are present in normal thyroid or cancer cells and there is limited information regarding response to treatment with vitamin D.

SV40 immortalized follicular cells (N-thy) and six thyroid cancer cell lines were treated with 10 µM vitamin D(3), 0.1 µM 1,25(OH)(2)D(3) or vehicle × 24 h. CYP27A1, CYP2R1, CYP27B1 and CYP24A1 mRNA were measured using quantitative real-time-PCR before and after treatment.

Cell proliferation was also evaluated in TPC1 and C643 cells after treatment with D(3), 25(OH)D(3) and 1,25(OH)(2)D(3). Baseline CYP27A1 and CYP27B1 mRNA were present in all cells, CYP2R1 was higher and CYP24A1 mRNA was lower in cancer cell lines versus N-thy.

TPC1 cells had increased CYP24A1 mRNA levels when treated with both D(3) (3.49, p < 0.001) and 1,25(OH)(2)D(3) (5.05, p < 0.001). C643 cells showed increased CYP24A1 mRNA expression when treated with 1,25(OH)(2)D(3) (5.36, p < 0.001).

D(3), 25(OH)D(3) and 1,25(OH)(2)D(3) all significantly decreased cell proliferation in TPC1 and C643 cells.

Overall, both cancerous and N-thy cell lines express CYP27A1 and CYP2R1 in addition to CYP27B1, establishing the potential to metabolize D(3) to 1,25(OH)(2)D(3). Additionally, vitamin D(3), 25(OH)D(3) and 1,25(OH)(2)D(3) all had an antiproliferative effect on two thyroid cancer cell lines.

Copyright © 2012 S. Karger AG, Basel.

PMID: 22992568 PMCID: PMC4266378 DOI: 10.1159/000342093


Molecular and Cellular Endocrinology
Volume 215, Issues 1–2, 27 February 2004, Pages 31-38

Vitamin D and barrier function: a novel role for extra-renal 1α-hydroxylase

MartinHewisonaDanielZehnderaRonjonChakravertybJohn S.Adamsc
Division of Medical Sciences, Institute of Clinical Research, The University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, UK
Transplant Biology Research Center/Bone Marrow Transplantation Section, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Room B-131, Los Angeles, CA 90048, USA

Much recent attention has focused on the positive health benefits of vitamin D beyond its established role in calcium homeostasis. Epidemiology has highlighted the link between vitamin D deficiency and prevalent diseases such as common cancers and autoimmune disease. Furthermore, studies in vitro have shown that the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is a potent antiproliferative and immunosuppressive agent.

The net effect of this has been the generation and analysis of synthetic analogues of vitamin D for potential use in the treatment of cancers and other disorders including psoriasis. However, there is increasing interest in the impact that vitamin D may have on normal physiology above and beyond its classical effects on calcium homeostasis and bone metabolism. We have postulated that these ‘non-calcemic’ effects of vitamin D are dependent on extra-renal synthesis of 1,25(OH)2D3 via the enzyme 1α-hydroxylase at barrier sites throughout the body.

Here we present a review of the mechanisms associated with extra-renal 1α-hydroxylase, and we also speculate on how this ‘new’ physiological role for vitamin D may actually reflect an ancient function for this pluripotent secosteroid.

Vitamin D and barrier function: a novel role for extra-renal 1α-hydroxylase - ScienceDirect


Antiviral Res. 2017 Jan;137:93-101. doi: 10.1016/j.antiviral.2016.11.004. Epub 2016 Nov 10.
Vitamin D increases the antiviral activity of bronchial epithelial cells in vitro.

Telcian AG1, Zdrenghea MT2, Edwards MR1, Laza-Stanca V1, Mallia P3, Johnston SL3, Stanciu LA4.
Author information
Airways Disease Infection Section, National Heart and Lung Institute, Imperial College London, Medical Research Council, Asthma UK Centre in Allergic Mechanisms of Asthma, Centre for Respiratory Infections, London, UK.
Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca and Ion Chiricuta Oncology Institute, Cluj-Napoca, Romania. Electronic address:
Airways Disease Infection Section, National Heart and Lung Institute, Imperial College London, Medical Research Council, Asthma UK Centre in Allergic Mechanisms of Asthma, Centre for Respiratory Infections, London, UK; Imperial College Healthcare NHS Trust, London, UK.
Airways Disease Infection Section, National Heart and Lung Institute, Imperial College London, Medical Research Council, Asthma UK Centre in Allergic Mechanisms of Asthma, Centre for Respiratory Infections, London, UK; Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca and Ion Chiricuta Oncology Institute, Cluj-Napoca, Romania.

By modulating the antiviral immune response via vitamin D receptor, the active form of vitamin D (1,25-dihydroxyvitamin D, calcitriol) could play a central role in protection against respiratory virus infections. This in vitro study tested the hypothesis that respiratory viruses modulate vitamin D receptor expression in human bronchial epithelial cells and this modulation affects the antiviral response to exogenous vitamin D.

Human primary bronchial epithelial cells were infected with rhinoviruses and respiratory syncytial virus in the presence or absence of vitamin D.
Expression of vitamin D receptor, 1α-hydroxylase (1α(OH)ase), 24-hydroxylase (24(OH)ase), innate interferons, interferon stimulated genes and cathelicidin were measured by quantitative polymerase chain reaction. The antiviral effect of vitamin D on rhinovirus replication was determined by measurement of virus load. A direct inactivation assay was used to determine the antiviral activity of cathelicidin.

Both RV and RSV decreased vitamin D receptor and 24(OH)ase and, in addition, RSV increased 1α(OH)ase expression in epithelial cells. Vitamin D decreased rhinovirus replication and release, and increased rhinovirus-induced interferon stimulated genes and cathelicidin. Furthermore, cathelicidin had direct anti-rhinovirus activity.

Despite lower vitamin D receptor levels in rhinovirus-infected epithelial cells, exogenous vitamin D increased antiviral defences most likely via cathelicidin and innate interferon pathways.



鼻病毒和呼吸道合胞病毒(RSV)减少维生素D受体和24 (OH) ase,此外,RSV增加1α(OH) ase上皮细胞中表达。维生素D减少鼻病毒的复制和释放,增加鼻病毒诱导的干扰素刺激基因和抗菌肽。抗菌肽具有直接的抗鼻病毒活性。



Copyright © 2016. Published by Elsevier B.V.

Cathelicidin; Interferons; Respiratory viruses

Vitamin D increases the antiviral activity of bronchial epithelial cells in vitro. - PubMed - NCBI


J Periodontal Res. 2019 Aug;54(4):444-452. doi: 10.1111/jre.12646. Epub 2019 Feb 25.
Activation of vitamin D in the gingival epithelium and its role in gingival inflammation and alveolar bone loss.

Menzel LP1, Ruddick W1, Chowdhury MH1, Brice DC1, Clance R1, Porcelli E1, Ryan LK2, Lee J3, Yilmaz Ö4,5, Kirkwood KL6, McMahon L7, Tran A7, Diamond G1.

Both chronic and aggressive periodontal disease are associated with vitamin D deficiency. The active form of vitamin D, 1,25(OH)2 D3 , induces the expression of the antimicrobial peptide LL-37 and innate immune mediators in cultured human gingival epithelial cells (GECs). The aim of this study was to further delineate the mechanism by which vitamin D enhances the innate defense against the development of periodontal disease (PD).

Wild-type C57Bl/6 mice were made deficient in vitamin D by dietary restriction. Cultured primary and immortalized GEC were stimulated with 1,25(OH)2 D3 , followed by infection with Porphyromonas gingivalis, and viable intracellular bacteria were quantified. Conversion of vitamin D3 to 25(OH)D3 and 1,25(OH)2 D3 was quantified by ELISA. Effect of vitamin D on basal IL-1α expression in mice was determined by topical administration to the gingiva of wild-type mice, followed by qRT-PCR.

Dietary restriction of vitamin D led to alveolar bone loss and increased inflammation in the gingiva in the mouse model. In primary human GEC and established human cell lines, treatment of GEC with 1,25(OH)2 D3 inhibited the intracellular growth of P. gingivalis. Cultured GEC expressed two 25-hydroxylases (CYP27A1 and CYP2R1), as well as 1-α hydroxylase, enabling conversion of vitamin D to both 25(OH)D3 and 1,25(OH)2 D3 . Topical application of both vitamin D3 and 1,25(OH)2 D3 to the gingiva of mice led to rapid inhibition of IL-1α expression, a prominent pro-inflammatory cytokine associated with inflammation, which also exhibited more than a 2-fold decrease from basal levels in OKF6/TERT1 cells upon 1,25(OH)2 D3 treatment, as determined by RNA-seq.

Vitamin D deficiency in mice contributes to PD, recapitulating the association seen in humans, and provides a unique model to study the development of PD. Vitamin D increases the activity of GEC against the invasion of periodontal pathogens and inhibits the inflammatory response, both in vitro and in vivo. GEC can convert inactive vitamin D to the active form in situ, supporting the hypothesis that vitamin D can be applied directly to the gingiva to prevent or treat periodontal disease.

© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

antimicrobial peptide; inflammation; periodontal disease; vitamin D

Activation of vitamin D in the gingival epithelium and its role in gingival inflammation and alveolar bone loss. - PubMed - NCBI


MP are protein molecules that are found in all organisms having potent anti-microbial activity. They are most abundantly found in keratinocytes, sebocytes and sweat glands. There are two types of AMPs. 1- Cathelicidins and 2- Defensins The only known human cathelicidin is LL-37(Schauber and Gallo 2008). These molecules are responsible for stopping antimicrobial invasion of skin, recruit immune cells for providing adaptive immune response and innate immune response. They induce apoptosis in athogenic and cancerous cells.






唯一已知的人类抗菌肽是LL-37(Schauber和Gallo 2008)。



What are endogenous antimicrobial peptides (AMP)? - Medicalopedia

Published: 09 November 2016
Potent Inducers of Endogenous Antimicrobial Peptides for Host Directed Therapy of Infections

H. Ottosson, F. Nylén, P. Sarker, E. Miraglia, P. Bergman, G. H. Gudmundsson, R. Raqib, B. Agerberth & R. Strömberg
Scientific Reports volume 6, Article number: 36692 (2016) Cite this article

A new concept for treatment of infections is induction of our own antimicrobial peptides and the presented novel class of inducer, aroylated phenylenediamines (APDs), gives up to 20 to 30-fold induction of the human antimicrobial peptide LL-37, in vitro. In addition, oral administration of an APD in a rabbit model of Shigellosis resulted in recovery from the infection in a few days implying that APD’s are promising candidates for treatment of infections.

Infectious diseases, especially those caused by bacteria resistant to antibiotics, are a serious threat to society. Globally, infections caused 20% of all deaths in 2010 and among children of 1 month to 4 years of age 66–70% of all deaths were due to infections1. Diarrheal disease, tuberculosis and lower respiratory tract infections led to 5.4 million deaths in the same year1. New antibiotics have yet to match this threat, and too few novel agents have been developed in the last decades2,3. Clearly, alternative approaches to treat infections should be investigated. Host directed therapy against pathogens by boosting the expression of endogenous antimicrobial peptides (AMPs) is a novel alternative for treatment of infectious diseases. Induction of multiple AMPs would minimize the risk of microbial resistance and during the existence of mankind resistance to this “mixture” of AMPs has not been developed4. AMPs are crucial components of innate defences and are produced constitutively and/or at epithelial surfaces, where the initial contact with microbes takes place5. AMPs possess a broad activity against various pathogens, i.e. viruses, bacteria, fungi, and parasites6.

There are two major classes of mammalian AMPs, the defensins (α- and β-families)7 and the cathelicidins8. Besides the microbicidal activity, AMPs also modulate immune responses9. The human cathelicidin LL-37 can be considered a marker for antimicrobial peptide expression and this peptide has been shown to also inhibit the formation and accelerate disintegration of bacterial biofilms10. In addition, LL-37 was shown to work in synergy with the antibiotic azithromycin towards multi-drug resistant gram negative bacteria11. Recently it has been demonstrated that autophagy is activated by LL-3712. The expression of AMPs is downregulated by specific pathogens13. On the other hand, butyrate14 and 4-phenylbutyrate (PBA)15 upregulate the expression of AMPs in epithelial cells and in macrophages. In addition, 1,25-Dihydroxyvitamin D3 (vitD) enhances the expression of LL-3716,17 and in a synergistic manner with PBA15. Induction by butyrate or PBA resulted in pathogen elimination and improved clinical symptoms in a rabbit model of shigellosis18,19 and of enteropathogenic E. coli (EPEC) induced diarrhea20. Adjunct therapy of PBA and vitD together with conventional TB antibiotics demonstrated beneficial effects towards clinical recovery in tuberculosis21. These findings suggest that the concept of induction of AMPs can be a complement to antibiotics in the treatment of infections.






有两个主要类别的哺乳动物抗菌肽,defensins(α-和β-families) 7 cathelicidins8。除了杀菌活性外,AMPs还调节免疫应答。人抗菌肽LL-37可作为抗菌肽表达的标记物,该肽已被证明可抑制细菌生物膜的形成,加速细菌生物膜的解体。此外,LL-37与阿奇霉素对多药耐药革兰氏阴性菌有协同作用。最近有研究表明,LL-3712可以激活自噬。AMPs的表达受特异性病原体的影响而下调13。另一方面,丁酸盐和4-苯基丁酸盐(PBA)上调了上皮细胞和巨噬细胞中AMPs的表达。此外,1,25-二羟基维生素D3 (vitD)增强了LL-37的表达,并与PBA协同作用。丁酸盐或PBA诱导的shigellosis和大肠杆菌(EPEC)致腹泻家兔模型均能消除致病菌,改善临床症状。PBA、vitD联合常规抗结核药物对结核患者的临床康复有积极作用。这些发现表明,AMPs的概念可以作为抗生素治疗感染的补充。


Potent Inducers of Endogenous Antimicrobial Peptides for Host Directed Therapy of Infections | Scientific Reports


Antimicrobial Peptides and Innate Lung Defenses
Role in Infectious and Noninfectious Lung Diseases and Therapeutic Applications

Pieter S. Hiemstra, PhD∗,'Correspondence information about the author PhD Pieter S. HiemstraEmail the author PhD Pieter S. Hiemstra, Gimano D. Amatngalim, Anne M. van der Does, PhD, Christian Taube, MD, PhD
Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands

Respiratory infections are a major clinical problem, and treatment is increasingly complicated by the emergence of microbial antibiotic resistance. Development of new antibiotics is notoriously costly and slow; therefore, alternative strategies are needed.

Antimicrobial peptides, central effector molecules of the immune system, are being considered as alternatives to conventional antibiotics. These peptides display a range of activities, including not only direct antimicrobial activity, but also immunomodulation and wound repair.

In the lung, airway epithelial cells and neutrophils in particular contribute to their synthesis. The relevance of antimicrobial peptides for host defense against infection has been demonstrated in animal models and is supported by observations in patient studies, showing altered expression and/or unfavorable circumstances for their action in a variety of lung diseases.

Importantly, antimicrobial peptides are active against microorganisms that are resistant against conventional antibiotics, including multidrug-resistant bacteria.

Several strategies have been proposed to use these peptides in the treatment of infections, including direct administration of antimicrobial peptides, enhancement of their local production, and creation of more favorable circumstances for their action.

In this review, recent developments in antimicrobial peptides research in the lung and clinical applications for novel therapies of lung diseases are discussed.


Pieter S. Hiemstra博士,‘关于作者Pieter S. hiemstrae博士的通信信息,电邮作者Pieter S. Hiemstra博士,Gimano D. Amatngalim, Anne M. van der Does博士,克里斯蒂安陶贝博士,MD, PhD









Antimicrobial Peptides and Innate Lung Defenses - CHEST