Literature overview nutritional components and their effect on the immune system via RXR binding partners: RAR, VDR, LXR, and PPAR

ReceptorNutritional ActivatorConcentration and Mode of AdministrationType of StudyModelStimulant/Disease ModelEffectReference
RARAll-trans RA1000 nMIn vitroHuman immature DCs with the Langerhans cells phenotypeInflammatory cytokines, RARα antagonist BMS 614 and pan-RAR antagonist BMS493DC apoptosis in the absence of inflammatory stimuli and DC activation in the presence of inflammatory stimuli(Geissmann et al., 2003)
All-trans RA10 nMIn vitro/ex vivoThymocytes from DO‐11.10 αβTCR‐Tg mice with a RAG‐2–deficient and B10.D2 background, and MHC class I and II double KO miceThymocytes 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 RA10 nMIn vitroNaïve T cells and DCs from DO‐11.10 x RAG‐2−/− B10.D2, normal B10.D2, and BALB/c miceCultured with normal medium, under Th1 conditions or Th2 conditions. In T cell–DC cocultures, ovalbumin was used. RARα antagonist LE135Enhanced α4β7 integrin and CCR9 expression and suppressed expression of E-selectin ligands on T cells(Iwata et al., 2004)
All-trans RA2 or 10 nMIn vitroHuman cord blood CD4+CD25 T cells, CD4+ T cells and CD11c+ DCs from BALB/c or AKR/J micePhytohemagglutinin, concanavalin A, IL-2, and RARα antagonist Ro41-5253Upregulation of FoxP3+ T cells(Kang et al., 2007)
Vitamin A1 or 10 nMIn vitro/ex vivoCD4+ T cells from WT or CCR9−/− BALB/c mice with excessive, normal, or deficient vitamin A statusConcanavalin A, IL-2, and RAR agonists and antagonists. Some experiments included TGF-β1Induction of Itg-α4, important for T-cell
(Kang et al., 2011)
All-trans RA1 or 10 nMIn vitroDCs from BALB/cJ miceCharacterized fetal bovine serum, granulocyte-macrophage colony-stimulating factor and RARα antagonist AGN 194301Downregulation of CD11a and increase in MMP-9 production(Lackey et al., 2008)
All-trans RA100 nMIn vitroCD4+ CD25 T cells from OT-II transgenic mice (C57BL/6 background)TGF-β, ovalbumin, and RARα antagonist LE135Inhibition 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)
RA2.5 nMIn vitro/ex vivoT cells from C57BL/6J WT and RARα-deficient miceIL-2, anti-CH3 with or without anti-CD28 antibodiesConversion of naïve T cells into FoxP3+ T regulatory cells(Nolting et al., 2009)
RA10 nMIn vitro/ex vivoB cells isolated from dnRARαCD19Cre and dnRARα miceMice immunized with hapten acetyl-cholera toxinInduction of B cells to produce IgA antibodies(Pantazi et al., 2015)
All-trans RA1000 nMIn vitroCoculture CD172a+ monocytes and lymphocytes from Swiss White Landrace pigsRARα antagonist Ro-41-5253Upregulation of β7 integrin and CCR9 in lymphocytes(Saurer et al., 2007)
All-trans RA1 µMIn vitroT cells from BALB/c miceRARα antagonist Ro41-5253Increased expression of FoxP3+ cells even in Th17-favoring conditions(Schambach et al., 2007)
RA5 or 25 nMIn vitroB cells from BALB/c miceTGF-β1 and RARα antagonist LE540Promotion 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)
RA25 nMIn vitroHuman tonsillar B cellsRARα antagonist LE540Promotion of IgA isotype switching in B cells(Seo et al., 2014)
RA10 nMIn vitroCD4+ CD25 T cells from C57B/6 STAT6-deficient or WT miceIL-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 regionReversion of STAT6 inhibition of the TGF-β1–mediated FoxP3 induction(Takaki et al., 2008)
All-trans RA10 nMIn vitro/ex vivoDCs from BALB/c, C57BL/6, DO11.10/RAG−/−, BALB/c IL13−/−, vitamin A(−), and vitamin A(+) miceOVA peptide P323-339 and RARα antagonists LE135 and LE540Prevention of IL-13, IL-17A, TNF-α, and INF-γ production by Th cells(Yokota-Nakatsuma et al., 2014)
VDRVitamin D325–100 nMIn vitroMouse primary peritoneal macrophagesLPS and siRNA-VDR transfectionNLRP3 activation and IL-1β release(Cao et al., 2020)
1,25(OH)2D3100 nMIn vitroHuman 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 miceStimulation dependent on cell line/type usedRegulation of primate innate immunity and induced expression of the antimicrobial peptide cathelicidin(Gombart et al., 2005)
1,25(OH)2D30.001–10 nMIn vitro/ex vivoBMDC from C57BL/6, WT and vitamin D null mutant miceInhibition of surface MHCII and costimulatory ligands B7-1, B7-2, and CD40(Griffin et al., 2000)
1,25(OH)2D31–100 nMIn vitroPrimary human monocytes/macrophages/DCsIntracellular M. tuberculosis/M. tuberculosis–derived lipopeptide and VDR-antagonist ZK159222 or Cyp27B1 antagonistProtection against M. tuberculosis via cathelicidin activation. A link between TLRs and vitamin D–mediated innate immunity(Liu et al., 2006)
1,25(OH)2D30.5–1.25 µMIn vitroHuman blood mononuclear cellsKetoconazole and VDR antagonist ZK191784 and ZK203278Accumulation of phospholipase Cγ1, T-cell growth, and proliferation(von Essen et al., 2010)
1,25(OH)2D31 nMIn vitroHuman cell lines, SCC25, Calu-3, and U937, human adult and neonatal primary keratinocytes, human monocytes, and neutrophilsE. Coli or P. aeruginosaInduction of antimicrobial peptides cathelicidin and defensin β2(Wang et al., 2004)
1,25(OH)2D310–100 nMIn vitro/ex vivoRAW264.7 cells and macrophages from COX2 WT and VDR KO C57BL/6/Sv129 miceLPSSuppression of Akt/NF-κB/COX-2(Wang et al., 2014)
1,25(OH)2D350 ng (diet) or 100 nM (ex vivo)In vivo/ex vivoC57BL/6 WT and VDR KO mice and iNKT cells/splenocytes ex vivoαGalCerVDR 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)2D325-50 ng/day/mouse (diet)In vivoCypKO and WT C57BL/6 miceαGalCer (intraperitoneal)1,25(OH)2D3 needed for normal NKT cell development(Yu and Cantorna, 2011)
1,25(OH)2D32, 20, and 50 nMIn vitroHuman PBMC and THP-1 cellsLPS 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)
LXR22(R)-hydroxy-cholesterol and 25-hydro xycholesterol20 µl of 10 nM each earIn vivoCD1 and LXRα−/−, LXRβ−/−, LXRα/β−/− C57Bl/6 miceTPA-induced contact dermatitis or oxazolone-induced dermatitisDecrease in ear thickness, inflammation of dermis and epidermis, and proinflammatory cytokines TNF-α and IL-1α(Fowler et al., 2003)
Cyanidin-3-O-β-glucoside10, 20, or 40 µMIn vitroMurine alveolar macrophagesLPS 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 cholesterol5 µMIn vitro/ex vivoRAW264.7 cells and macrophages from LXRαβ+/+ mice, LXRαβ−/− mice, or WT C57BL/6 miceLPS 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 cholesterol2 µMIn vitro/ex vivoRAW264.7 cells and peritoneal macrophages from WT and LXR-null C57BL/6 miceLPS or Escherichia coliInhibition of inducible NOS(Joseph et al., 2003)
22R-hydroxy cholesterol and 25-hydroxy cholesterolUnspecifiedIn vitroHuman DCs and
HepG2 cells
LPS and shRNA-LXRαInhibition of CCR7 expression(Villablanca et al., 2010)
PPARDHA20 µMIn vitroRAW264.7 and Jurkat T cellsLPS or zymosan A and siRNA-PPARγIncreased expression of M2 markers, enhanced efferocytosis, and decrease in M1 markers(Chang et al., 2015)
Chrysin1–100 µMIn vitroANA-1, RAW264.7, HEK-293 cells, and peritoneal macrophages from obese miceLPS, IL-4, and PPARγ-specific antagonist GW9662Decrease in M1 markers and increase in M2 markers(Feng et al., 2014)
Apigenin7.5 µMIn vitroANA-1, RAW264.7, HEK-293 cells, and murine primary peritoneal macrophagesLPS or IL-4, PPARγ-specific antagonist GW9662, and shRNA-PPARγFavoring M2 polarization via inhibition of NF-κB(Feng et al., 2016)
EPA0.1, 0.5, or 1.0 g/kg i.p.In vivo/ex vivoC57BL/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 etherReduced 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 DHA25, 50, or 100 µMIn vitroHuman PBMC, Th-cell assaysPMA,ionomycin and PPARγ-specific antagonist T0070907Reduction of IL-2, IL-4, and TNF-α in Th cells (DHA to a lesser extent than EPA)(Jaudszus et al., 2013)
DHA50 µMIn vitroBone marrow–derived DCs from C56BL/6 miceLPS and PPARγ-specific antagonist GW9662Immature DC phenotype and inhibition of IL-12 via inhibition of NF- κBp65 nuclear translocation(Kong et al., 2010)
EPA and DHA10 and 100 µMIn vitroHK-2 cellsLPS and PPARγ-specific antagonist bisphenol A diglycidyl etherDecrease in LPS-induced MCP-1 in an NF-κB–dependent manner(Li et al., 2005)
PA and DHA0.5 mM PA and 50 µM DHAIn vitroRAW264.7 cellsLPS and PPARγ-specific antagonist GW9662Increased M2 markers dependent on the PPAR-γ and NF-κBp65 signal pathway(Luo et al., 2017)
Oxidized EPA500 µl 3.3 mMIn vivoWT and PPARα−/− 129SV miceLPSInhibited rolling and adhesion in neutrophils and monocytes(Sethi et al., 2002)
EPA100, 250, or 500 mg/kg/day i.p.In vivo/ex vivoBALB/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 GW9662Prolonged 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)
DHA50 µMIn vitroMonocytes (differentiated into DCs) and lymphocytes from human PBMCStimulation dependent on assay and PPARγ-specific antagonist GW9662Downregulation 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.