Table 1.
The immunomodulatory roles of vitamins, reported by experimental studies.
| Vitamins | Dose/Concentration | Study Model | Findings | References |
|---|---|---|---|---|
| Vitamin A | 500 nM | In vitro (peripheral blood mononuclear cells) | RA inhibits IFN-γ, IL-17, and IL-9 production in CD4+ T cells, upregulates CD103 expression and gut-homing receptors | [44] |
| 0.1 μM | In vitro (peripheral blood mononuclear cells) | RA prevents human nTregs from converting to Th1 and/or Th17 cells and sustains their Foxp3 expression and suppressive function, suppresses IL-1 receptor (IL-1R) upregulation, accelerates IL-6R downregulation | [45] | |
| 0.01 M | In vitro (myelomonocytic cells) | Retinoids inhibit mumps virus in vitro due to upregulation of type I interferon (IFN) and IFN stimulated genes | [108] | |
| Concentration in olive oil suspension 25 mg/mL and inject intraperitoneally 125 μg/gm weight | In vivo (Mice) | Retinoic acid acts intrinsically in developing gut- tropic premucosal dendritic cell, directs generation of intestine-like cDC1 and cDC2 subsets | [109] | |
| retinyl acetate (25 µg/d) | In vivo (Mice) | Effective for clearance of Citrobacter rodentium, fewer CD8αβ+ cells and more CD8αα+ and T cell receptor (TCR)γδ+ T cells, enhanced IL17 | [110] | |
| 5 or 25 nM | In vitro (Human tonsillar B cells) | Increases IgA production, the expression of germ-line IgA1, IgA2 transcripts (GLTa1 and GLTa2), and the frequency of IgA1-secreting B cell clones, and induces IgA isotype switching | [111] | |
| 1 µM retinol | In vitro (Murine respiratory tract lung epithelial cell) | Increases IgA production by lipopolysaccharide (LPS)-stimulated splenocytes cultures, and increases the expression of MCP-1, IL-6, and GM-CSF | [112] | |
| Control diet of retinol palmitate 15 IU/g | In vivo (Mice) | Causes reduction of immunodominant CD8+ T cell frequencies in the lower respiratory tract (LRT) airways of VAD animals, T cells, and shows unusually high CD10 | [113] | |
| 1 μM | In vivo (mouse splenocytes) | Lowers Th17 T-cell activity, downregulating IL-6, promoting B cell production of IgA, upregulating IL-6, and increasing transcript levels of MCP-1, GMCSF, and IL-10 in MACs | [114] | |
| 0 or 15 IU g−1 vitamin A |
In vivo (Mice) | Increases cytokine/chemokine gene expression and cytokine protein production in VAD animals. Viral infection persists longer in the upper and lower respiratory tract of VAD mice | [115] | |
| 250 µg per day | In vivo (transgenic mice) | Regulates the homeostasis of pre-Dendritic cell (DC)–derived DC subsets and have implications for the management of immune deficiencies | [116] | |
| 0 or 15 IU/g vitamin A palmitate | In vivo (Mice) | VAS decreases death and diarrhea-related mortalities in children, and increases immune responses toward pediatric vaccines | [117] | |
| 0 to 25,000 IU kg−1 | In vivo (Mice) | Controls local lymphoid tissue inducer cell differentiation and maturation upstream of the transcription factor RORct | [118] | |
| 10 nM RA | In vivo (Mice) | Abrogates RA signaling in B cells; these cells were not able to induce a4b7 expression. RA signaling in B cells is important for the induction of IgA+ GC, effective gut humoral response, and to maintain a normal microbiota composition. It has a direct effect on IgA plasma cell differentiation | [119] | |
| 60 mg/kg | In vivo (Mice) | Lowers interferon (IFN)-g production, activates NKT cells, decreases extracellular signal-regulated kinase (ERK) phosphorylation, and enhances phosphatase 2A (PP2A) activity | [120] | |
| Vitamin C | 2 mg/kg, 150 mg/kg | In vivo (piglets) | Decreases vulva length, width, height, and area,. Decreses the concentrations of BUN, CRE, AST and TBIL in serum, and reduces IgA, IgG and IgM levels. Restoring serum estradiol (E2), progesterone (PROG), luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in weaning piglets | [121] |
| 50 to 200 mg/kg/24 h. | In vitro (venous blood sample) | Increases the expression of the antimicrobial proteins, ↓MtDNA levels | [122] | |
| 200 mg/kg | In vivo (Mice) | Decreases lung neutrophil extracellular traps, decreases circulating free-DNA following peritonitis-induced sepsis. In vitamin C deficient neutrophils, Upregulates endoplasmic reticulum stress associated gene expression, Induces autophagy signaling and increases PAD4 mRNA | [123] | |
| 162 ± 8 mg vitamin C per 100 g fruit | In vitro (venous blood) | No effect on control (non-stimulated) neutrophil migration, increases neutrophil oxidative burst, improvement of important neutrophil functions | [124] | |
| 57 mg/kg/day | In vivo (Mice IRI) | Lowers the severity of tubular injury and renal arterial resistance | [125] | |
| 100 nM | In vitro (peripheral blood mononuclear cells) | Increases oxidative stress, lowers proinflammatory mediator, ROS, TNF-α,and IL-6, LPS-Induced Autophagy in MH-S Cell Lines | [126] | |
| 200 mg/kg | In vivo (Mice) | Prevents sepsis-mediated disassembly of the Na+-K+-ATPase pump, causes cytoskeletal rearrangements, changes in viscoelastic properties, increases epithelial ion channel and transporter expression, and increases alveolar fluid clearance | [127] | |
| 3.3 g/L | In vivo (Mice) | Increases type I interferons (IFNs), increases IFN-α and -β, increases infiltration of inflammatory cells (IL-1α/β and TNF-α) into the lung | [128] | |
| Vitamin D | 1 to 100 nM | In vitro (peripheral B cell line) | Increases IgE production by 63.9 ± 5.9%., decreases CD19+ CD27high CD38+ B cell population, and decreases AID expression | [129] |
| 0.1 μM, 1.0 μM, 10 μM | In vitro (human PBMCs) | Lowers T helper (Th) cell population-specific cytokine expression of interferon γ (Th1), interleukins IL-17A (Th17) and IL-22 (Th17/Th22), ↑IL-4 (Th2) levels | [130] | |
| (6 µg/kg/day in PBS/0.03% ethanol) | In vivo (Mice) | Lowers the IgE response in a type I allergy mouse model | [129] | |
| n.m | In vitro (PBMCs) | Causes inhibition of IgE production by calcitriol is mediated by its transrepressive activity through the VDR-corepressor complex | [131] | |
| 0.05–50 mg/kg 25(OH)D | In vivo (mice) | Decreases the allergic airway inflammation, Th2 cytokine expression in the lungs. And the humoral immune reaction | [132] | |
| 0–50 nM | In vivo (Mice) and human PBMCs | Decreases CD8 and CD4 T cells proliferation, and IL-2, ↓IFN-γ and ↓IL-17 production, increases IL-4 and IL-10 production and human Treg development | [133] | |
| 25(OH)cholecalciferol (40 ng/mL) or 1,25(OH)2cho- lecalciferol (20 ng/mL) | In vitro (peripheral blood mononuclear cells) | Lowers interleukin (IL)-9, IL-5, and IL-8. Increases IL-13þ cells, downregulates transcription factors PU.1 and interferon regulatory factor 4 | [134] | |
| 10−9 M, 10−8 M or 10−7 M | In vitro (Primary bronchial epithelial cells) | Causes suppression of viral replication, and increases LL-37 expression | [135] | |
| 5(OH)D(<50 nmol/L, 50–75 nmol/L ≥75 nmol/L) | In vitro (peripheral blood mononuclear cells) | Reduces systemic inflammation | [136] | |
| 100, 10 or 1 ng/mL of vitamin D3 | In vitro (human monocytes) | Upregulates the expression of NK cytotoxicity receptors NKp30 and NKp44, as well as NKG2D, downregulates the expression of the killer inhibitory receptor CD158, and downregulates the expression of CCR6 on the surface of iDCs | [137] | |
| 10 nM 1,25D3 | In vitro (peripheral blood mononuclear cells) | inhibits the cytokine response of CD40L-stimulated macrophages, decreases CD40L-induced expression, decreases tumor necrosis factor (TNF)-α production, decreases interleukin (IL)-1β production, and (IFN)- γ proliferation, and increases IL-10 production | [138] | |
| Vitamin D3 (cholecalciferol) at >2000 IU/kg | In vivo (Mice) | 1,25(OH)2D3/VDR-dependent induction of IL-10 production can contribute to the mast cell’s ability to suppress inflammation and skin pathology at sites of chronic UVB irradiation | [139] | |
| four fortnightly doses of 2.5 mg vitamin D3 | In vitro | Increases chemokines (AMP MMP-9) and antigen-stimulated Th1 cytokine suppression, decreases IL-4, CCL5, and IFN-α secretion, accelerates sputum smear conversion, and enhances treatment-induced resolution of lymphopenia, monocytosis, hypercytokinemia, and hyperchemokinemia | [140] | |
| 10−8 M | In vivo (Mice) | Restrains the inflammatory response of NOD and C57BL/6 BM-derived DCs, decreases secretion of CCL3, CCL4, CCL5, and CXCL10, increases secretion of CCL2 and CCL7, decreases T cell stimulatory capacity, and increases migration-competent tolerogenic DCs | [141] | |
| 1 μg/kg VD | In vivo (Mice) | Upregulates p53 acetylation-mediated apoptosis in MH7A cells, promotes Sirt1 translocation and apoptosis of FLSs | [142] | |
| 100/30 nM | In vitro (Human alveolar epithelial cell line) | Decreases autophagy, enhances apoptosis, decreases H1N1-induced TNF-α level, IFN-b (interferon-beta), and IFN-stimulated gene-15. Downregulates IL-8 as well as IL-6 RNA levels and suppresses the H1N1- induced transcription | [143] | |
| 10 or 100 nM | In vitro (peripheral blood mononuclear cells) | Causes suppression of NK cytotoxicity and downregulation of CD107a expression in NK cells, increases CD158a and CD158b expression, decreases the expression of NKp30 and NKp44 on CD56+CD3− NK cells, and lowers CD56+/IFN- γ+ and CD56+/TNF-α+ | [144] | |
| 100 nmol | In vitro (bronchial epithelial cell line) | Decreases rhinovirus replication and release, and increases rhinovirus-induced interferon stimulated genes and cathelicidins | [145] | |
| 100,000 IU of cholecalciferol per week for 4 weeks, followed by 100,000 IU of cholecalciferol per month for 6 months | In vitro (SLE patients) | Increases naïve CD4+ T cells and regulatory T cells, decreases effector Th1 and Th17 cells, and decreases memory B cells and anti-DNA antibodies | [146] | |
| 5 ng/mL | In vitro (peripheral blood mononuclear cells) | Increases Foxp3+ and IL-10+ CD4+T cells | [147] | |
| Vitamin E | TRF supplements (200 mg each capsule) 400 mg per day | In vitro (human blood leukocytes) | Enhances production of IFN-y, f IL-4, IL-6, and TNF-α | [148] |
| 50 mg/d | In vivo (Human) | Decreases incidence of pneumonia by 69% | [149] | |
| 1 kg of T3 supplemented diet (1 g Tocomin 50% +39 g vitamin E- stripped soybean oil + 0.96 kg basal die) | In vivo (Mice) | Increases splenocyte IL-1b production, Lymphocyte proliferation, tumor necrosis factor-a, and interferon-ꭚ | [150] | |
| 50–200 μg /mL | In vitro (human PBMCs) | Increases cAMP production, IL-2 production, IL-17, IL-8, and RANTES | [151] | |
| 30 or 500 ppm of vitamin E (RRR-a-Tocopheryl acetate) | In vivo (Mice) | Gamma-T was more effective but less specific than alpha-T in the presence of vitamin E; CD40L is strongly upregulated by alpha-T, but down-regulated by gamma-T, gamma-T appears to better prevent e induction of gene expression upon T cell stimulation, e.g. of some cytokines (interleukin 3 and 10) and chemokines (chemokine ligand 9, 10, and 11) | [152] | |
| 250 to 500 mg D-α-tocopherol/kg diet | In vivo (Mice) | Decreases lung CD11b+ dendritic cell subsets, lung mRNA expression of IL-4, IL-33, TSLP, CCL11, and CCL24 | [153] | |
| 30 (control) or 500 (supplemented) ppm of vitamin E | In vivo (Mice) | Increases the expression of genes (Ccnb2, Cdc2, Cdc6) in old T cells. Increases upregulation of IL-2 expression, decreases upregulation of IL-4, has impact on signal transduction, transcriptional regulation, and apoptosis pathways in T cells | [154] | |
| 46 mmol/L of vitamin E | In vitro (Mice spleen cells) | Vitamin E eliminates the age-related differences in LAT phosphorylation in both T cell subsets, and difference in the tyrosine phosphorylation of LAT | [155] | |
| Vitamin K | vitamin K (1–5 μM) | In vitro (Bone marrow-derived macrophages) | Causes inhibitors of the NLRP3 inflammasome to block the interaction between NLRP3 and ASC, which attenuates the severity of inflammation | [156] |
| MK-4 (0.5–20 μmol/L) | In vitro (microglial cell line (BV2)) | Suppresses the upregulation in the expression of iNOS and COX-2 in the cells and the production of TNF-α and IL-1β. Inhibits ROS production, p38 activation, and rotenone-induced nuclear translocation of NF-κB in BV2 cells | [157] | |
| 20 mM menadione | In vitro (Mice Splenocytes) | Increases ROS levels, thus suppressing production in lymphocytes and CD4 + T cells, and activation of ERK, JNK and NF- κB | [158] | |
| Vitamin K2 | In vitro (human bladder cancer cell lines) | Induces apoptosis in bladder cancer cells, generates reactive oxy- gen species (ROS), phosphorylating of c-Jun N-terminal kinase (JNK) and p38 MAPK | [159] | |
| 0.1–100 μM | In vitro (PBMCs) | Suppressing the mitogen-activated proliferation, inhibiting the production of tumor necrosis factor (TNF) α, interleukin (IL)-4, -6, and -10, and increases Treg cells | [160] | |
| Vitamin B1 | (0 µg/mL, 0.125 µg/mL, 0.25 µg/mL, 0.5 µg/mL, 1 µg/mL, and 2 µg/mL) | In vitro (breast epithelial cells from non-cancer origin and metastatic site) | Reduces extracellular lactate levels, increases cellular pyruvate dehydrogenase (PDH) activities, decreases non-glycolytic acidification, glycolysis, and glycolytic capacity, and reduces cell proliferation in MCF7 | [161] |
| Not mentioned | In vitro (Mice encephalitogenic cells) | TD aggravated the development of EAE, causing microglial activation, increases leukocyte infiltration in the spinal cord, Th1, and Th17 cells, and upregulates expression of CCL2 | [162] | |
| complete chow (303.3 ± 42.6 nmol/L) thiamine deficiency | In vivo (Mice) | Thiamine deficiency increases TNF-α and MCP-1 concentrations, decreases blood IL-1β level, and increases KC, IL-1 β, and IL-6 | [163] | |
| Vitamin B2 | low (3·1 nM), physiological (10·4 nM) or high (300 and 531 nM) | In vivo (mouse monocyte/macrophage cell line) | Low riboflavin content decreases the proliferation rate and increases apoptotic cell death, completely inhibits the respiratory burst and slightly impairs phagocytosis, and impairs cell adhesion | [164] |
| 3.1 nM to 10.4 nM | In vivo (Mycoplasma-free mouse preadipocytes) | Riboflavin deprivation Induces adipocyte death, increases lipolysis and free fatty acid release, ROS Production, NF-κB Phosphorylation, and pro-inflammatory TNFα and IL-6 | [165] | |
| 1 µg/mL, 0.5 µg/mL, 0.25 µg/mL, 0.125 µg/mL, 0.62 µg/mL, 0.31 µg/mL, 0.15 µg/mL and untreated control 0 µg/mL for vitamin B2 | In vitro (U937 cell line) | Inhibits cell migration of pro-Monocytic cells, decreases the expression of PD-L1, increases secretion of IL-8 and IL-10, and increases GM-CSF | [166] | |
| Vitamin B3 | 100 mg/kg/d niacin | In vivo (guinea pigs) | Downregulates inflammatory factors (IL-6 and TNF-α), suppresses protein expression of CD68 and NF-κB p65, attenuates oxidative stress | [167] |
| 10−3–10−6 M Nicotinic acid | In vitro (preadipocytes cells) | attenuating expression of fractalkine, MCP-1, RANTES, iNOS, and macrophage chemotaxis | [168] | |
| Niacin (0–1 mM) | In vitro (human aortic endothelial cells) | Inhibits production of ROS, LDL oxidation, TNF-α, NF-κB activation, and vascular cell adhesion molecule-1 (VCAM-1) | [169] | |
| Nicotinic acid (0.1–3 mM) | In vitro (human monoblastic leukemia cell line) | Induces macrophage PGD2 secretion | [170] | |
| 80 and 320 mg/kg | In vivo (rats) | Increases colonic MPO activity and TNF-α level, and decreases cytokine IL-10 | [171] | |
| 100 mg and 250 mg niacin | In vivo | Causes macrophage polarization from M1 (pro-inflammatory) to M2 (counter-inflammatory), boosting anti-inflammatory processes, thus suppressing inflammation | [172] | |
| niacin (1, 10, 100 μmol/l) | In vitro (Murine alveolar macrophages) | reduces the levels of TNF-α, IL-6 and IL-1β in LPS-challenged alveolar macrophages, inhibits NF-κB activation, attenuates the LPS-induced pro-inflammatory cytokines | [173] | |
| niacin (0.25–1 mM) | In vitro (umbilical vein endothelial cells) | Decreases IL-6 and TNF-α secretion and inhibits NF-κB p65 and notch1 protein expression | [167] | |
| Vitamin B5 | 10 µM | In vivo (C57BL/6J mice) | significantly inhibits the growth of Mycobacterium tuberculosis by regulating innate immunity and adaptive immunity | [62] |
| Vitamin B6 | (1000 µg/mL, 500 µg/mL, 250 µg/mL, 125 µg/mL, 62.5 µg/mL, 31.25 µg/mL, 15.6 µg/mL | In vitro (U937 cell line) | Inhibit cell migration and proliferation of pro-monocytic cells, decreases the expression of PD-L1 and IL-1β, and increases secretion of IL-8 and IL-10 | [166] |
| 0, 12 mg, and 120 mg per kg diets | In vivo (male BALB/c mice) | Vitamin B6 deficiency decreases growth rate, lymphocyte proliferation, and CD4 T Lymphocyte Differentiation | [66] | |
| 5, 10, 20, and 40 mg/kg | In vivo (Rex rabbits) | Increases IL-2, IFN-γ, M cell number, weight of thymus and spleen, cell division, prolifferation, and maturation | [68] | |
| 100 nM PMA, B6 vitamer (500 µM) | In vivo (Mice) | Vitamin B6 inhibits LPS-induced NF-κB, JNK activation, and gene expression, suppresses NLRP3 inflammasome activation, noncanonical IL-1β secretion and pyroptosis, and inhibits signal 1 and signal 2 for the IL-1β production | [69] | |
| Vitamin B7 | 0.8 mg d-biotin per kg | In vivo (mice) | Biotin deficiency upregulates TNF-α production; however, no differences were detected in NF-κB activity | [174] |
| basal diet (0.8 mg/kg of d-biotin) biotin deficient (biotin free) |
In vivo (Mice) | Improves Ni allergy, increases PUFA in rat liver, decreases IL-1b production and proliferation, and decreases TNF-α production | [175] | |
| Control (d-biotin 0.2 mg/L) BD (biotin free) |
In vitro (murine macrophage cell line) | Inhibits augmentation of IL-1b production | [175] | |
| 0, 10 and 100 µM biotin | In vitro (Human dendritic cells) | BD enhancing TNF-α, IL-12p40, IL-23, and IL-1β secretion, and IFN-γ and IL-17 induction | [176] | |
| Vitamin B9 | (2 mg/kg diet) | In vivo (Mice) | Decreases total T cells and NK cell, increases TNFα immunoreactive protein, and increases liver Abca1 mRNA | [177] |
| 0.2 to 25 ppb | In vivo (Mice) | In vitro, vit-B9 reduces condition differentiated Treg cells from naïve cells but fails to survive. In vivo, depletion of vit B9 results in reduction of Treg cells in small intestine | [178] | |
| (1000 µg/mL, 500 µg/mL, 250 µg/mL, 125 µg/mL, 62.5 µg/mL, 31.25 µg/mL, 15.6 µg/mL and | In vitro (U937 cell line) | Exerts an anti-tumorigenic effect, inhibits cell migration, proliferation of Pro-Monocytic Cells, lowers the expression of PD-L1, and increases secretion of IL-8 and IL-10 | [166] | |
| 5 mg Folic Acid | In vivo | Increases UMFA concentrations and decreases the number and cytotoxicity of NK cells | [179] | |
| control medium (100 ng/mL) low folate medium (10 ng/mL) and no folate medium |
In vitro (mouse monocyte cell line) | Folate deficiency enhances the pro-inflammatory cytokine increase in pro-inflammatory marker expression, blunts the generation of nitric oxide in response to an LPS challenge | [180] | |
| Vitamin B12 | 0.3 μM | In vivo (Mice) | B12 lessens kidney IRI, decreases kidney inflammation and fibrosis, DNA damage response (DDR) and apoptosis, and hypoxia/reperfusion (H/R) injury, and modulates H/R induced chemokine gene expression | [181] |
| 2–64 μM | In vitro | Exerts robust protection against 30 μM concentrations of the pro-oxidants homocysteine and hydrogen peroxide, inhibits intracellular peroxide production, and prevents apoptotic and necrotic cell death | [182] | |
| low (<250 pg/mL) and normal (>250 pg/mL) vitamin B12 | In vitro (PBMCs) | Low vitamin-12 level increases production of IL-6, IFN-γ | [183] | |
| 10–50 nM | In vitro (Primary HAEC) | Prevents homocysteine-induced increases in O2•− and cell death, homocysteine and rotenone-induced mitochondrial O2•− production | [184] | |
| Not mention | In vivo (Mice) | Increases CD8+ T cells, decreases CD4/CD8 ratio, and decreases T reg in control groups than pre and post treatment groups. | [185] | |
| Not mention | Cross- sectional study | Negatively associated with TNF-α, HOMA-IR, serum resistin (children) and positively associated with pro-inflammatory cytokines and biochemical markers | [186] | |
| 300% of the daily intake | In vivo (rats) | Decreased negative impact of protein malnutrition facilitates the production of T lymphocytes | [187] | |
| 1000 µg/day intramuscularly | In vivo | Restoring increased CD4/CD8 ratio and depressed NK cell activity, increases C3, C4, and immunoglobulins | [75] |