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. 2014 Mar;30(2):144–150.

Effect of Vitamin D3 on Monocyte Chemoattractant Protein 1 Production in Monocytes and Macrophages

Yi-Chen Wang 1*, Chong-Chao Hsieh 2*, Hsuan-Fu Kuo 3, Ming-Kai Tsai 4,5, San-Nan Yang 6,7,8, Chang-Hung Kuo 6,7,9, Min-Sheng Lee 7,9#, Chih-Hsing Hung 6,7,8,10#
PMCID: PMC4805020  PMID: 27122781

Abstract

Background

Chemokine is important in the initiation and progression of atherosclerosis, the clinically manifest stages of atherosclerosis and acute coronary syndrome. Vitamin D deficiency has been reportedly linked with hypertension and myocardial infarction, as well as other cardiovascular-related diseases, such as congestive heart failure, peripheral vascular disease and atherosclerosis. Monocyte chemoattractant protein 1 (MCP-1) mediates atherosclerosis and other cardiovascular diseases. However, there have been few studies conducted about the role of 1α,25-(OH)2D3 on MCP-1 expression in human monocytes.

Methods

We investigated the effects of vitamin A, C and 1α,25-(OH)2D3, three common vitamins, to better ascertain MCP-1 expression in human monocyte and also the associated intracellular mechanism. Human monocyte cell line (THP-1 cell) and THP-1 cell-induced macrophage were treated with varying doses of vitamin A, C and 1α,25-(OH)2D3 for 2 hours before LPS stimulation. Supernatants were harvested to measure MCP-1 levels by the enzyme-linked immunosorbent assay (ELISA). The intracellular mechanism about the effects of vitamin A, C and 1α,25-(OH)2D3 on the expression of MCP-1 expression in human monocytes was assessed by western blot.

Results

We found that Lipopolysaccharides (LPS)-induced MCP-1 production was suppressed by 1α,25-(OH)2D3 in THP-1 cells and THP-1-induced macrophage. Only high concentration of vitamin A and C could reduce LPS-induced MCP-1 production in THP-1-induced macrophage, but not in THP-1 cells. LPS-induced p38 expression in THP-1 cells was suppressed by 1α,25-(OH)2D3. A selective p38 pathway inhibitor SB203580 could also suppress LPS-induced MCP-1 production. However, vitamin D receptor blocking antibody could reverse the suppressive effect of 1α,25-(OH)2D3 on MCP-1 expression.

Conclusions

These data demonstrate that 1α,25-(OH)2D3 is effective in down-regulating LPS-induced MCP-1. The suppressive effect on MCP-1 may, at least in part, involve the vitamin D receptor and down-regulation of LPS - induced p38 expression.

Keywords: Chemokine, Monocyte chemoattractant protein 1 (MCP-1), Monocyte, p38, Vitamin D

INTRODUCTION

Good nutritional intake may have an anti-inflammatory effect and be beneficial to the management of cardiovascular diseases (CVDs). For example, in a rat study, compared with normal chow and safflower oil, fish oil attenuated collagen deposition, macrophage infiltration, transforming growth factor (TGF)- β expression, apoptosis, and tissue levels of arachidonic acid, macrophage inflammatory protein (MIP)-1, interleukin interleukin (IL)-1, monocyte chemoattractant protein (MCP)-1 and leukotriene B.1 Vitamin D is a steroid-like hormone that is related to phosphate and calcium metabolism. Vitamin D does not occur naturally in the human body and is acquired through foods such as fortified dairy products and cereals, oily fish and fish liver oils and exposure to sunlight, predominantly from precursors within the skin through the action of ultraviolet B radiation on 7-dehydrocholesterol.2 Vitamin D has been shown to exist in 2 major forms: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Notably, the active form of vitamin D, 1α,25-dihydroxy vitamin D3 (1α,25-(OH)2D3) exerts most of the biological effects associated with vitamin D.3 Epidemiological studies have highlighted the increasing prevalence of vitamin D3 deficiency and its association with increased risks of CVDs, e.g. atherosclerosis,4-7 however, the effect of vitamin D3 supplementation on preventing CVDs remains controversial.8 The immunomodulatory properties of vitamin D3 have been recognized beyond their well-established role in bone and calcium metabolism. The active form of vitamin D3 induces Tregs and tolerogenic dendritic cells (DCs), which are both involved in maintaining immunological tolerance to self and harmless antigens.4

Atherosclerosis is a chronic inflammatory disorder affecting large- and medium-sized arteries, and the leading cause of mortality worldwide. The pathogenesis of atherosclerosis involves the accumulation of lipids and leukocytes in the intima of blood vessel walls with plaque.9 Just why the leukocytes accumulate in plaque remains poorly understood; however, chemokines appear to be important in this process. Inflammation is an essential hallmark during the development of atherosclerosis, for which major leukocytes infiltrated in the lesions are monocytes and macrophages. Chemokines are a family of small (8- to 10-kDa), secreted, usually inducible proteins which are involved in leukocyte recruitment and critical for leukocyte homeostasis.10 Chemokines play essential roles during inflammatory responses and pathogenesis for atherosclerosis.10 MCP-1, a potent monocyte attractant, exerts its effects through binding to G-protein-coupled receptors on the surface of leukocytes targeted for activation and migration. The role of MCP-1 and its receptor CC chemokine receptor 2 (CCR2) in monocyte recruitment during infection or under other inflammatory conditions is well known.11 Therefore, MCP-1 and its primary receptor CCR2 are the targets for gene therapy to inhibit monocyte/macrophage-mediated inflammation in atherogenesis.12

Since MCP-1 regulation is important for increased risks of CVDs, e.g. atherosclerosis-triggered inflammatory reaction and cardiac remodeling, it is reasonable to evaluate the effect of 1α,25-(OH)2D3 on the monocyte-related chemokines in monocytes because several studies suggest 1α,25-(OH)2D3 has an anti-inflammatory effect. We will also explore the detailed mechanisms of intracellular signaling, including MAPK and NFkB pathway.

METHODS

Cell preparation

The human monocytic cell line THP-1 (American Type Culture Collection, Rockville, MD, USA) was cultured in RPMI 1640 medium (Sigma Chemical Co., St. Louis, MO, USA) with 10% fetal bovine serum, 100 U/mL of penicillin, and 100 μg/mL of streptomycin at 37 °C and 5% CO2 in a humidified incubator. Cells were centrifuged and resuspended in fresh media in 24-well plates at a concentration of 106/mL for 24 h before experimental use. To induce the differentiation of THP-1 macrophages, THP-1 monocytes were cultured in complete culture medium containing 100 nM phorbol-12-myristate-13-acetate (Sigma, USA) for 72 hours.13 The THP-1 cells and macrophage induced by THP-1 cells were pre-treated with varying doses of vitamin A, C or 1α,25-(OH)2D3 (Sigma ChemicalCo. St.Louis, MO, USA) for 2 hours before LPS (0.2 μg/ml) (Escherichia coli; Sigma Chemical Co., St. Louis, MO, USA) stimulation. In some cases, THP-1 cells were pre-treated with a selective p38 pathway inhibitor SB203580 or vitamin D receptor blocking the antibody one hour before 1α,25-(OH)2D3 (Sigma Chemical Co., St. Louis, MO, USA). Polyinosinic-polycytidylic acid [poly(I:C)] is a synthetic analog of double-stranded RNA (dsRNA), a molecular pattern mimicking viral infection. Cell supernatant was collected at different time points after LPS or poly I:C stimulation. The production of cytokines in the culture supernatants was determined for MCP-1.

ELISA assay

The MCP-1 concentrations of cell supernatants were determined using commercially available ELISA-based assay systems (R&D System, Minneapolis, MN, USA). Assays were performed using the protocols recommended by the manufacturer.

Western blotting

After treatment for 2 h with or without 1α ,25-(OH)2D3, the cells were stimulated with LPS (0.2 μg/ml) and lysed with equal volumes of ice-cold 150-μl lysis buffer 1 h later. After centrifugation at 13,000 × g for 15 min, equal amounts of cell lysates were analyzed by Western blot with anti-p65, anti-phospho-p65, anti-MAPK (p38, ERK and JNK) and anti-phospho-MAPK (pp38, p-ERK and p-JNK) antibodies (Santa Cruz Biotechnology, Santa Cruz, CA, USA). Immunoreactive bands were visualized using horseradish peroxidase-conjugated secondary antibody and the enhanced chemiluminescence (ECL) system (Amersham Pharmacia Biotech, now part of GE Lifesciences).

Statistical analyses

All data are presented as mean ± SD. The differences between experimental and control groups were analyzed by using the Mann-Whitney test. A p value < 0.05 was considered indicative of significant between-group differences.

RESULTS

Vitamin D3, but not vitamin A or vitamin C, decreased MCP-1 production in THP-1 cells

1α,25-(OH)2D3 (1-10 μM) and significantly down-regulated LPS-induced MCP-1 production in THP-1 cells after LPS stimulation for 6, 24 and 48 h (Figure 1A, B and C). However, the same finding was not observed in vitamin A (Figure 2A, B and C) and vitamin C (Figure 3A, B and C) at the same treatment time course (6, 24 and 48 h).

Figure 1.

Figure 1

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1α,25-(OH)2D3 significantly suppressed LPS-induced MCP-1 production in THP-1 cells after LPS stimulation for 6 h (A), 24 h (B) and 48 h (C) (* p < 0.05).

Figure 2.

Figure 2

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Vitamin A could not down-regulate LPS-induced MCP-1 production in THP-1 cells after LPS stimulation for 6 h (A), 24 h (B) and 48 h (C).

Figure 3.

Figure 3

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Vitamin C could not decrease LPS-induced MCP-1 production in THP-1 cells after LPS stimulation for 6 h (A), 24 h (B) and 48 h (C).

Vitamin D3 decreased MCP-1 in THP-1-induced macrophages

We found that 1α ,25-(OH)2D3 (1-10 μM) significantly down-regulated LPS-induced MCP-1 production in THP-1-induced macrophages after LPS stimulation for 24 and 48 h (Figure 4A and B). The similar and more profound effect could be found in poly I:C-induced MCP-1 production in THP-1-induced macrophages after poly I:C stimulation for 24 and 48 h even with very lower dose (0.1 μM) of 1α,25-(OH)2D3 treatment (Figure 5A and B).

Figure 4.

Figure 4

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1α,25-(OH)2D3 significantly suppressed LPS-induced MCP-1 production in THP-1-induced macrophages after LPS stimulation for 24 h (A) and 48 h (B) (* p < 0.05, # p < 0.01, † p < 0.001).

Figure 5.

Figure 5

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1α,25-(OH)2D3 inhibited poly I:C-induced MCP-1 production in THP-1 macrophages after LPS stimulation for 24 h (A) and 48 h (B).

Vitamin A and C (10 μM) decreased MCP-1 in THP-1-induced macrophages

Low dose of vitamin A (0.1-1 μM) significantly up-regulated LPS-induced MCP-1 production in THP-1-induced macrophages after LPS stimulation for 24 h (Figure 6A). However, a relatively higher dose of vitamin A (10 μM) significantly down-regulated LPS-induced MCP-1 production in THP-1-induced macrophages after LPS stimulation for 24 h (Figure 6A). Vitamin A (1-10 μM) significantly down-regulated LPS-induced MCP-1 production in THP-1-induced macrophages after LPS stimulation for 48 h (Figure 6B). Vitamin C had no effect on LPS-induced MCP-1 production in THP-1-induced macrophages after LPS stimulation for 24 h (Figure 7A). However, Vitamin C (10 μM) decreased LPS-induced MCP-1 production in THP-1-induced macrophages after LPS stimulation for 48 h (Figure 7B).

Figure 6.

Figure 6

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Vitamin A regulated LPS-induced MCP-1 production in THP-1-induced macrophages after LPS stimulation for 24 h (A). Vitamin A (1-10 μM) significantly decreased LPS-induced MCP-1 production in THP-1 macrophages after LPS stimulation for 24 h (B).

Figure 7.

Figure 7

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Vitamin C had no effect on LPS-induced MCP-1 production in THP-1-induced macrophages after LPS stimulation for 24 h (A). Vitamin C (10 μM) decreased LPS-induced MCP-1 production in THP-1-induced macrophages after LPS stimulation for 48 h (B).

Vitamin D3 suppressed LPS-induced MCP-1 production via p38 pathway in THP-1 cells

Mitogen-activated protein kinases (MAPK) and nuclear Factor-KappaB (NfkB) pathway are the main signaling avenues for LPS (toll-like receptor 4 agonist) and poly I:C (toll-like receptor 3 agonist) stimulation.14 Figure 8 showed that 1α,25-(OH)2D3 suppressed LPS-induced pp38, but not pp65 pJNK or pERK on THP-1 cells. Therefore, the suppressive effect of 1α,25-(OH)2D3 on LPS-induced MCP-1 expression in THP-1 cells is, at least in part, through p38 MAPK pathway.

Figure 8.

Figure 8

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1α,25-(OH)2D3 suppressed LPS-induced pp38, but not pJNK, pERK or pp65 expression in THP-1 cells.

Selective p38 inhibitor SB203580 suppressed LPS-induced MCP-1 production and vitamin D receptor blocking antibody reversed the suppressive effect of 1α,25-(OH)2 vitamin D3 on LPS-induced MCP-1 production in THP-1 cells.

To further confirm the suppressive effect of 1α,25-(OH)2 vitamin D3 on LPS-induced MCP-1 expression in THP-1 cells through p38 MAPK pathway, THP-1 cells were pre-treated with a selective p38 pathway inhibitor SB203580 before 1α,25-(OH)2 vitamin D3. SB203580 (1 and 10 μM) could significantly suppress LPS-induced MCP-1 production for 24 h (Figure 9A) and 48 h (Figure 9B) in THP-1 cells. Vitamin D receptor blocking antibody reversed the suppressive effect of 1α,25-(OH)2 vitamin D3 on LPS-induced MCP-1 production in THP-1 cells (Figure 9C). Therefore, the suppressive effect of 1α,25-(OH)2 vitamin D3 on LPS-induced MCP-1 production was, at least in part, through vitamin D receptor.

Figure 9.

Figure 9

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A selective p38 pathway inhibitor SB203580 (1 and 10 μM) could significantly suppress LPS-induced MCP-1 production for 24 h (A) and 48 h (B) in THP-1 cells. A selective vitamin D receptor blocking antibody could reverse the suppressive effect of 1α,25-(OH)2 vitamin D3 on LPS-induced MCP-1 production (C).

DISCUSSION

Atherosclerotic CVDs are a major source of mortality and morbidity throughout the world. Oxidative modification of low-density lipoprotein cholesterol (LDL-C) is one of the most important determinant factors in the development and progression of atherosclerotic lesions.15 Metabolic syndrome is associated with dysfunctional adipose tissue that is most likely a consequence of the enlargement of adipocytes and infiltration of macrophages into adipose tissue. Enlargement of adipocytes leads to a chronic state of inflammation in the adipocytes associated with increase of the secretion of proinflammatory cytokines such as IL-6, IL-8 and MCP-1. These proinflammatory cytokines may substantially affect cardiovascular function and morphology.16 Macrophage infiltration may lead to a chronic low grade, systemic, inflammatory state associated with cardiovascular events. Furthermore, the inflammation triggered by visceral fat may contribute to an increased risk of vascular complications. Therapies that target macrophage accumulation or secretory products of adipose tissue may be potentially beneficial in reducing the vascular risk associated with obesity. MCP-1 is a potential therapeutic target for atherosclerotic CVDs and is a potent chemokine that is elevated in obesity.17

The link between LDL and CVDs has been widely studied. Appropriate nutritional practices are of central importance in managing risk and treatment of CVDs; in fact, many current guidelines for a healthy general population contain nutritional recommendations to reduce the risk of CVDs. Oxidized LDL damages the artery wall, and a diet rich in vitamins and low in saturated fat and cholesterol may reduce this risk. Not only hypercholesterolemia but also low levels of high density lipoprotein cholesterol are critical risk factors for atherosclerosis and related diseases. Some vitamins may provide important lipid soluble anti-oxidants in humans, and reduce atherosclerosis plaque, coronary artery diseases and myocardial infarction.18 In the present study, the suppressive effect of vitamin A, C and D on LPS-induced MCP-1 production in monocytes or macrophages suggested the potential role of vitamin s on the treatment or prevention of atherosclerosis and other CVDs. Observational studies of vitamins C, the most prevalent natural antioxidant vitamin, suggest that supplemental use of these vitamins may lower the risk for coronary events. Despite these data, several large, randomized controlled trials have failed to confirm the benefits of vitamin C in cardiovascular disease prevention.19 In our data, only higher dose of vitamin C had suppressive effect on MCP-1 production in THP-1 macrophages, but not THP-1 cells.

Cardiovascular diseases and adverse events are significantly higher in subjects with very low vitamin D levels, including coronary artery disease, heart failure, atrial fibrillation, peripheral artery disease, stroke, and myocardial infarction. Additionally, the rate of death is significantly higher in subjects with very low vitamin D levels.20-22 Vitamin D deficiency could be an independent risk factor for the development of peripheral arterial disease and this risk factor is easily correctable.23 Our data also suggested that vitamin suppressed LPS-induced MCP-1 production in monocytes or macrophages with different potency. Vitamin D may be more powerful and could be still effective in very low concentration. The active form of vitamin D3, 1, 25(OH)2-dihydroxyvitamin D3 (calcitriol), and its analogue inhibited autoimmune disease in animal models via inducing tolerogenic DCs and Tregs.24-27 Therefore, for the prevention of CVDs, 25(OH)2-dihydroxyvitamin D3 may be the good choice. In the present study, vitamin D3 has a more profound effect on poly I:C (Toll-like 3)-related signaling than LPS (Toll-like 4)-mediated pathway. Several studies have reported a relationship between the development of atherosclerosis and the presence of infectious diseases, widely occurring in the general population, often chronic or asymptomatic.29-31 Beyond Chlamydia pneumoniae, a large number of infectious agents have been linked with an increased risk of vascular disease, including Helicobacter pylori, influenza A virus, herpes virus, hepatitis C virus, cytomegalovirus, and human immunodeficiency virus. Infections may induce atherosclerosis either via direct infection of vascular cells or via the indirect effects of cytokines or acute phase proteins induced by infection at “nonvascular” sites.32 Vitamin D3 may play an important role in the prevention or treatment for virus-induced inflammation in monocytes or macrophages.

CONCLUSIONS

This study demonstrated that 1α,25-(OH)2D3 is effective in down-regulating LPS-induced MCP-1 in monocyte-macrophage. The suppressive effect on MCP-1 may, at least in part, involve vitamin D receptor and the down-regulation of LPS - induced p38 expression.

Acknowledgments

This study was supported by grants from Medical Research Fund (No. 101-06 and 101-03) of Kaohsiung Armed Forces General Hospital and from National Science Council (NSC 99-2314-B-037-014-MY3) of the Republic of China and a grant from Kaohsiung Municipal Ta-Tung Hospital KMTTH-101-007.

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