The Influence of Vitamin A Supplementation on Foxp3 and TGF-β Gene Expression in Atherosclerotic Patients

The aim of this study was to investigate the role of vitamin A in Foxp3 and TGF-β gene expression in atherosclerotic patients. Patients and healthy controls in the vitamin A group received 25,000 IU retinyl palmitate per day, while patients in the placebo group took one capsule of placebo per day for 4 months. Gene expressions of regulatory T cells were studied by real-time PCR. The levels of Foxp3 expression in phytohemagglutinin-activated cells were much higher in the patients who received vitamin A than in placebo-treated patients and healthy controls, while Foxp3 gene expression in oxidized low-density lipoprotein-activated cells showed no significant differences between all groups (p = 0.357). A significant difference in the expression level of TGF-β gene in fresh cells was observed between patients and healthy controls (p = 0.009). TGF-β gene expression in oxidized low-density lipoprotein-activated cells increased in all groups; however, these changes were not statistically significant (p = 0.65); the changes obtained were 2.8-, 2.2- and 3.9-fold in the vitamin A, placebo, and control groups, respectively. Based on suppressing actions of regulatory T cells on effector T cells and findings that show that vitamin A has the effect of increasing expression of regulatory T cells, it can be concluded that supplementation with vitamin A in atherosclerotic patients may be effective in slowing disease progression.

[1]  M. Kuroki,et al.  Activation of TGF-β1 Through Up-Regulation of TSP-1 by Retinoic Acid in Retinal Pigment Epithelial Cells , 2008, Current eye research.

[2]  Yuka Kanno,et al.  Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. , 2008, Blood.

[3]  H. Mishima,et al.  Role of TGF-beta in the retinoic acid-induced inhibition of proliferation and melanin synthesis in chick retinal pigment epithelial cells in vitro. , 2001, Cell biology international.

[4]  Hilde Cheroutre,et al.  Reciprocal TH17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid , 2007, Science.

[5]  R. D. Hatton,et al.  Contrasting roles for all-trans retinoic acid in TGF-β–mediated induction of Foxp3 and Il10 genes in developing regulatory T cells , 2009, The Journal of experimental medicine.

[6]  A. Tedgui,et al.  Inhibition of Transforming Growth Factor- Signaling Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Mice , 2001 .

[7]  H. Mishima,et al.  ROLE OF TGF‐β IN THE RETINOIC ACID‐INDUCED INHIBITION OF PROLIFERATION AND MELANIN SYNTHESIS IN CHICK RETINAL PIGMENT EPITHELIAL CELLS IN VITRO , 2001 .

[8]  Chang H. Kim.  Regulation of FoxP3+ Regulatory T Cells and Th17 Cells by Retinoids , 2008, Clinical & developmental immunology.

[9]  Kazuko Kobayashi,et al.  Oxidative modification of low-density lipoprotein and immune regulation of atherosclerosis. , 2006, Progress in lipid research.

[10]  Y. Belkaid,et al.  Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid , 2007, The Journal of experimental medicine.

[11]  G. Keren,et al.  Altered status of CD4(+)CD25(+) regulatory T cells in patients with acute coronary syndromes. , 2006, European heart journal.

[12]  R. Morris,et al.  Relationship between classic risk factors, plasma antioxidants and indicators of oxidant stress in angina pectoris (AP) in Tehran. , 2000, Atherosclerosis.

[13]  C. Kuntz,et al.  Monocytes influence the fate of T cells challenged with oxidised low density lipoproteins towards apoptosis or MHC-restricted proliferation. , 2001, Atherosclerosis.

[14]  P. Teeling,et al.  Low Numbers of FOXP3 Positive Regulatory T Cells Are Present in all Developmental Stages of Human Atherosclerotic Lesions , 2007, PloS one.

[15]  A. Tedgui,et al.  Cytokine network and T cell immunity in atherosclerosis , 2009, Seminars in Immunopathology.

[16]  J. George.  Mechanisms of Disease: the evolving role of regulatory T cells in atherosclerosis , 2008, Nature Clinical Practice Cardiovascular Medicine.

[17]  M. Ballow,et al.  Retinoic Acid Enhances the Production of IL-10 While Reducing the Synthesis of IL-12 and TNF-α from LPS-Stimulated Monocytes/Macrophages , 2007, Journal of Clinical Immunology.

[18]  H. Broxmeyer,et al.  Vitamin A Metabolites Induce Gut-Homing FoxP3+ Regulatory T Cells1 , 2007, The Journal of Immunology.

[19]  M. Daemen,et al.  Transforming growth factor-beta mediates balance between inflammation and fibrosis during plaque progression. , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[20]  H. Kagechika,et al.  Effect of Synthetic Retinoid, TAC-101, on Experimental Autoimmune Disease , 2002, Pharmacology.

[21]  Retinoic Acid Increases Foxp3+ Regulatory T Cells and Inhibits Development of Th17 Cells by Enhancing TGF-β-Driven Smad3 Signaling and Inhibiting IL-6 and IL-23 Receptor Expression1 , 2008, The Journal of Immunology.

[22]  J. Plutzky,et al.  Retinoid metabolism and its effects on the vasculature. , 2012, Biochimica et biophysica acta.

[23]  A. Tedgui,et al.  Regulatory T cell responses: potential role in the control of atherosclerosis , 2005, Current opinion in lipidology.

[24]  Y. Belkaid,et al.  A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β– and retinoic acid–dependent mechanism , 2007, The Journal of experimental medicine.

[25]  Yong Chen,et al.  The Th17/Treg imbalance in patients with acute coronary syndrome. , 2008, Clinical immunology.

[26]  P. Albert,et al.  Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. , 1995, Journal of immunology.

[27]  A. Lalvani,et al.  Regulatory T cells are expanded in blood and disease sites in patients with tuberculosis. , 2006, American journal of respiratory and critical care medicine.

[28]  R. Noelle,et al.  All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation , 2007, The Journal of experimental medicine.

[29]  Zhanju Liu,et al.  All-trans Retinoic Acid Down-regulates Inflammatory Responses by Shifting the Treg/th17 Profile in Human Ulcerative and Murine Colitis , 2009 .

[30]  A. Lichtman,et al.  The influence of the regulatory T lymphocytes on atherosclerosis. , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[31]  R. Flavell,et al.  Natural regulatory T cells control the development of atherosclerosis in mice , 2006, Nature Medicine.

[32]  G. Keren,et al.  Role of Naturally Occurring CD4+CD25+ Regulatory T Cells in Experimental Atherosclerosis , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[33]  B. Lim,et al.  Retinoic Acid Increases Foxp3+ Regulatory T Cells and Inhibits Development of Th17 Cells by Enhancing TGF-β-Driven Smad3 Signaling and Inhibiting IL-6 and IL-23 Receptor Expression1 , 2008, The Journal of Immunology.

[34]  D. Grainger,et al.  Dietary fat and reduced levels of TGFbeta1 act synergistically to promote activation of the vascular endothelium and formation of lipid lesions. , 2000, Journal of cell science.

[35]  A. Nègre-Salvayre,et al.  Mildly oxidized low-density lipoproteins suppress the proliferation of activated CD4+ T-lymphocytes and their interleukin 2 receptor expression in vitro. , 1998, The Biochemical journal.

[36]  Peter Libby,et al.  Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis , 2002, Circulation research.

[37]  Samuel A. M. Martin,et al.  Identification of two FoxP3 genes in rainbow trout (Oncorhynchus mykiss) with differential induction patterns. , 2010, Molecular immunology.

[38]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[39]  A. Rudensky,et al.  Foxp3 programs the development and function of CD4+CD25+ regulatory T cells , 2003, Nature Immunology.

[40]  M. Lazar,et al.  Activation of retinoic acid receptor‐α favours regulatory T cell induction at the expense of IL‐17‐secreting T helper cell differentiation , 2007, European journal of immunology.

[41]  C. Stephensen,et al.  Diets rich in polyphenols and vitamin A inhibit the development of type I autoimmune diabetes in nonobese diabetic mice. , 2007, The Journal of nutrition.