Literature overview nutritional components and their effect on the immune system via RXR binding partners: RAR, VDR, LXR, and PPAR
| Receptor | Nutritional Activator | Concentration and Mode of Administration | Type of Study | Model | Stimulant/Disease Model | Effect | Reference |
|---|---|---|---|---|---|---|---|
| RAR | All-trans RA | 1000 nM | In vitro | Human immature DCs with the Langerhans cells phenotype | Inflammatory cytokines, RARα antagonist BMS 614 and pan-RAR antagonist BMS493 | DC apoptosis in the absence of inflammatory stimuli and DC activation in the presence of inflammatory stimuli | (Geissmann et al., 2003) |
| All-trans RA | 10 nM | In vitro/ex vivo | Thymocytes from DO‐11.10 αβTCR‐Tg mice with a RAG‐2–deficient and B10.D2 background, and MHC class I and II double KO mice | Thymocytes stimulated with ionomycin and phorbol myristate acetate, naïve T cells stimulated with cytokines for Th1/Th2 development. RARα antagonists LE135 and LE540 | Th2 promotion and Th1 suppression dependent on the timing of stimulation | (Iwata et al., 2003) | |
| All-trans RA | 10 nM | In vitro | Naïve T cells and DCs from DO‐11.10 x RAG‐2−/− B10.D2, normal B10.D2, and BALB/c mice | Cultured with normal medium, under Th1 conditions or Th2 conditions. In T cell–DC cocultures, ovalbumin was used. RARα antagonist LE135 | Enhanced α4β7 integrin and CCR9 expression and suppressed expression of E-selectin ligands on T cells | (Iwata et al., 2004) | |
| All-trans RA | 2 or 10 nM | In vitro | Human cord blood CD4+CD25− T cells, CD4+ T cells and CD11c+ DCs from BALB/c or AKR/J mice | Phytohemagglutinin, concanavalin A, IL-2, and RARα antagonist Ro41-5253 | Upregulation of FoxP3+ T cells | (Kang et al., 2007) | |
| Vitamin A | 1 or 10 nM | In vitro/ex vivo | CD4+ T cells from WT or CCR9−/− BALB/c mice with excessive, normal, or deficient vitamin A status | Concanavalin A, IL-2, and RAR agonists and antagonists. Some experiments included TGF-β1 | Induction of Itg-α4, important for T-cell migration | (Kang et al., 2011) | |
| All-trans RA | 1 or 10 nM | In vitro | DCs from BALB/cJ mice | Characterized fetal bovine serum, granulocyte-macrophage colony-stimulating factor and RARα antagonist AGN 194301 | Downregulation of CD11a and increase in MMP-9 production | (Lackey et al., 2008) | |
| All-trans RA | 100 nM | In vitro | CD4+ CD25− T cells from OT-II transgenic mice (C57BL/6 background) | TGF-β, ovalbumin, and RARα antagonist LE135 | Inhibition of IL-6–driven induction of proinflammatory Th17 cells, stimulation of anti-inflammatory FoxP3+ Treg cell differentiation, and upregulation of α4β7 integrin | (Mucida et al., 2007) | |
| RA | 2.5 nM | In vitro/ex vivo | T cells from C57BL/6J WT and RARα-deficient mice | IL-2, anti-CH3 with or without anti-CD28 antibodies | Conversion of naïve T cells into FoxP3+ T regulatory cells | (Nolting et al., 2009) | |
| RA | 10 nM | In vitro/ex vivo | B cells isolated from dnRARαCD19Cre and dnRARα mice | Mice immunized with hapten acetyl-cholera toxin | Induction of B cells to produce IgA antibodies | (Pantazi et al., 2015) | |
| All-trans RA | 1000 nM | In vitro | Coculture CD172a+ monocytes and lymphocytes from Swiss White Landrace pigs | RARα antagonist Ro-41-5253 | Upregulation of β7 integrin and CCR9 in lymphocytes | (Saurer et al., 2007) | |
| All-trans RA | 1 µM | In vitro | T cells from BALB/c mice | RARα antagonist Ro41-5253 | Increased expression of FoxP3+ cells even in Th17-favoring conditions | (Schambach et al., 2007) | |
| RA | 5 or 25 nM | In vitro | B cells from BALB/c mice | TGF-β1 and RARα antagonist LE540 | Promotion of IgA isotype switching in B cells. RA in combination with TGF-β1 enhanced expression of CCR9 and α4β7 on B cells | (Seo et al., 2013) | |
| RA | 25 nM | In vitro | Human tonsillar B cells | RARα antagonist LE540 | Promotion of IgA isotype switching in B cells | (Seo et al., 2014) | |
| RA | 10 nM | In vitro | CD4+ CD25− T cells from C57B/6 STAT6-deficient or WT mice | IL-2 (Th0 condition), TGF-β + IL2 (iTreg condition), or TGF-β + IL-2 + IL-4 + IL-10 (Th3 condition). Identification of the RA-responsive element in the FoxP3 promoter region | Reversion of STAT6 inhibition of the TGF-β1–mediated FoxP3 induction | (Takaki et al., 2008) | |
| All-trans RA | 10 nM | In vitro/ex vivo | DCs from BALB/c, C57BL/6, DO11.10/RAG−/−, BALB/c IL13−/−, vitamin A(−), and vitamin A(+) mice | OVA peptide P323-339 and RARα antagonists LE135 and LE540 | Prevention of IL-13, IL-17A, TNF-α, and INF-γ production by Th cells | (Yokota-Nakatsuma et al., 2014) | |
| VDR | Vitamin D3 | 25–100 nM | In vitro | Mouse primary peritoneal macrophages | LPS and siRNA-VDR transfection | NLRP3 activation and IL-1β release | (Cao et al., 2020) |
| 1,25(OH)2D3 | 100 nM | In vitro | Human myeloid leukemia cell lines, U937, NB4, HL60, ML1, human bone marrow–derived macrophages, human HaCat HT29, and U937 cells. Murine 32Dc13 cells and bone marrow cells from murine WT and VDR-deficient mice | Stimulation dependent on cell line/type used | Regulation of primate innate immunity and induced expression of the antimicrobial peptide cathelicidin | (Gombart et al., 2005) | |
| 1,25(OH)2D3 | 0.001–10 nM | In vitro/ex vivo | BMDC from C57BL/6, WT and vitamin D null mutant mice | — | Inhibition of surface MHCII and costimulatory ligands B7-1, B7-2, and CD40 | (Griffin et al., 2000) | |
| 1,25(OH)2D3 | 1–100 nM | In vitro | Primary human monocytes/macrophages/DCs | Intracellular M. tuberculosis/M. tuberculosis–derived lipopeptide and VDR-antagonist ZK159222 or Cyp27B1 antagonist | Protection against M. tuberculosis via cathelicidin activation. A link between TLRs and vitamin D–mediated innate immunity | (Liu et al., 2006) | |
| 1,25(OH)2D3 | 0.5–1.25 µM | In vitro | Human blood mononuclear cells | Ketoconazole and VDR antagonist ZK191784 and ZK203278 | Accumulation of phospholipase Cγ1, T-cell growth, and proliferation | (von Essen et al., 2010) | |
| 1,25(OH)2D3 | 1 nM | In vitro | Human cell lines, SCC25, Calu-3, and U937, human adult and neonatal primary keratinocytes, human monocytes, and neutrophils | E. Coli or P. aeruginosa | Induction of antimicrobial peptides cathelicidin and defensin β2 | (Wang et al., 2004) | |
| 1,25(OH)2D3 | 10–100 nM | In vitro/ex vivo | RAW264.7 cells and macrophages from COX2 WT and VDR KO C57BL/6/Sv129 mice | LPS | Suppression of Akt/NF-κB/COX-2 | (Wang et al., 2014) | |
| 1,25(OH)2D3 | 50 ng (diet) or 100 nM (ex vivo) | In vivo/ex vivo | C57BL/6 WT and VDR KO mice and iNKT cells/splenocytes ex vivo | αGalCer | VDR KO resulted in abnormal function and growth of natural killer T cells. Increase in IL-4 and IFN-γ by natural killer T cells. | (Yu and Cantorna, 2008) | |
| 1,25(OH)2D3 | 25-50 ng/day/mouse (diet) | In vivo | CypKO and WT C57BL/6 mice | αGalCer (intraperitoneal) | 1,25(OH)2D3 needed for normal NKT cell development | (Yu and Cantorna, 2011) | |
| 1,25(OH)2D3 | 2, 20, and 50 nM | In vitro | Human PBMC and THP-1 cells | LPS and siRNA-VDR transfection | Transformation of LPS-induced M1 macrophages to M2 macrophages by upregulation of IL-10, arginase-1, VDR and IFN regulatory factor 4 and downregulation of TNF-α, IL-6, and INF regulatory factor 5 phosphorylation | (Zhu et al., 2019) | |
| LXR | 22(R)-hydroxy-cholesterol and 25-hydro xycholesterol | 20 µl of 10 nM each ear | In vivo | CD1 and LXRα−/−, LXRβ−/−, LXRα/β−/− C57Bl/6 mice | TPA-induced contact dermatitis or oxazolone-induced dermatitis | Decrease in ear thickness, inflammation of dermis and epidermis, and proinflammatory cytokines TNF-α and IL-1α | (Fowler et al., 2003) |
| Cyanidin-3-O-β-glucoside | 10, 20, or 40 µM | In vitro | Murine alveolar macrophages | LPS and siRNA-LXRα transfection | Inhibited TNF-α, IL-1β, and IL-6 production by alveolar macrophages | (Fu et al., 2014) | |
| 22(R)-hydroxy cholesterol (22R), 24(S), 25 epoxy cholesterol, and 24-hydroxy cholesterol | 5 µM | In vitro/ex vivo | RAW264.7 cells and macrophages from LXRαβ+/+ mice, LXRαβ−/− mice, or WT C57BL/6 mice | LPS or poly I:C and siRNA-LXR transfection in RAW264.7 cells | Repression of inducible NOS via SUMOylation-dependent transrepression pathway | (Ghisletti et al., 2007) | |
| 22(R)-hydroxy cholesterol | 2 µM | In vitro/ex vivo | RAW264.7 cells and peritoneal macrophages from WT and LXR-null C57BL/6 mice | LPS or Escherichia coli | Inhibition of inducible NOS | (Joseph et al., 2003) | |
| 22R-hydroxy cholesterol and 25-hydroxy cholesterol | Unspecified | In vitro | Human DCs and HepG2 cells | LPS and shRNA-LXRα | Inhibition of CCR7 expression | (Villablanca et al., 2010) | |
| PPAR | DHA | 20 µM | In vitro | RAW264.7 and Jurkat T cells | LPS or zymosan A and siRNA-PPARγ | Increased expression of M2 markers, enhanced efferocytosis, and decrease in M1 markers | (Chang et al., 2015) |
| Chrysin | 1–100 µM | In vitro | ANA-1, RAW264.7, HEK-293 cells, and peritoneal macrophages from obese mice | LPS, IL-4, and PPARγ-specific antagonist GW9662 | Decrease in M1 markers and increase in M2 markers | (Feng et al., 2014) | |
| Apigenin | 7.5 µM | In vitro | ANA-1, RAW264.7, HEK-293 cells, and murine primary peritoneal macrophages | LPS or IL-4, PPARγ-specific antagonist GW9662, and shRNA-PPARγ | Favoring M2 polarization via inhibition of NF-κB | (Feng et al., 2016) | |
| EPA | 0.1, 0.5, or 1.0 g/kg i.p. | In vivo/ex vivo | C57BL/10, BALB/c and CBA mice, murine splenocytes (ex vivo) | Hearts from C57BL/10 or BALB/c mice transplanted into CBA mice and ex vivo PPARγ-specific antagonist bisphenol A diglycidyl ether | Reduced IL‐2, IFN‐γ, and IL‐12 and increased IL-10, number of CD4+CD25+ and CD4+CD25+Foxp3+ cells. | (Iwami et al., 2009) | |
| EPA and DHA | 25, 50, or 100 µM | In vitro | Human PBMC, Th-cell assays | PMA,ionomycin and PPARγ-specific antagonist T0070907 | Reduction of IL-2, IL-4, and TNF-α in Th cells (DHA to a lesser extent than EPA) | (Jaudszus et al., 2013) | |
| DHA | 50 µM | In vitro | Bone marrow–derived DCs from C56BL/6 mice | LPS and PPARγ-specific antagonist GW9662 | Immature DC phenotype and inhibition of IL-12 via inhibition of NF- κBp65 nuclear translocation | (Kong et al., 2010) | |
| EPA and DHA | 10 and 100 µM | In vitro | HK-2 cells | LPS and PPARγ-specific antagonist bisphenol A diglycidyl ether | Decrease in LPS-induced MCP-1 in an NF-κB–dependent manner | (Li et al., 2005) | |
| PA and DHA | 0.5 mM PA and 50 µM DHA | In vitro | RAW264.7 cells | LPS and PPARγ-specific antagonist GW9662 | Increased M2 markers dependent on the PPAR-γ and NF-κBp65 signal pathway | (Luo et al., 2017) | |
| Oxidized EPA | 500 µl 3.3 mM | In vivo | WT and PPARα−/− 129SV mice | LPS | Inhibited rolling and adhesion in neutrophils and monocytes | (Sethi et al., 2002) | |
| EPA | 100, 250, or 500 mg/kg/day i.p. | In vivo/ex vivo | BALB/c and C57BL/6 mice Mixed-lymphocyte reaction (splenocytes from donor BALB/c mice + lymph node cells from recipient mice) | Hearts from BALB/c mice transplanted into C57BL/6 mice and ex vivo PPARγ specific antagonist GW9662 | Prolonged graft survival due to increased Treg/Th17 ratios in donor heart. Decrease in IL-6 and IL-17 and increase in TGF-β production in mixed-lymphocyte reaction | (Ye et al., 2012) | |
| DHA | 50 µM | In vitro | Monocytes (differentiated into DCs) and lymphocytes from human PBMC | Stimulation dependent on assay and PPARγ-specific antagonist GW9662 | Downregulation of costimulation and antigen presentation resulting in immature phenotype with increased chemotactic abilities, inhibition of IL-6, IL-10, and IL-12 | (Zapata-Gonzalez et al., 2008) |
shRNA, short hairpin RNA; STAT, signal transducer and activator of transcription; HEK, Human Embryonic Kidney; THP-1, human monocytic leukemia.