Home LiteratureArticle Details
PMID: 20414208 Published · ppublish English Journal Article Review

Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells.

Nature reviews. Immunology ·Vol. 10 ·No. 5 ·2010-05-00 ·Pages 365-76

Glass CK, Saijo K

Abstract

Members of the nuclear receptor superfamily of ligand-dependent transcription factors regulate diverse aspects of immunity and inflammation by both positively and negatively regulating gene expression. Here, we review recent studies providing insights into the distinct mechanisms that enable nuclear receptors to antagonize pro-inflammatory programmes of gene expression in macrophages and T cells by altering the turnover or recruitment of co-repressors and co-activators in a gene-specific manner. These nuclear receptor-dependent transrepression pathways are proposed to have roles in controlling the initiation, magnitude and duration of pro-inflammatory gene expression and are amenable to pharmacological manipulation.

MeSH Terms
Animals Humans Inflammation/immunology Liver X Receptors Macrophages/immunology Nuclear Receptor Co-Repressor 1/physiology Nuclear Receptor Co-Repressor 2/physiology Orphan Nuclear Receptors/physiology PPAR gamma/physiology Receptors, Cytoplasmic and Nuclear/physiology Receptors, Glucocorticoid/physiology Repressor Proteins/physiology T-Lymphocytes/immunology Transcriptional Activation
Chemicals
Liver X Receptors NCOR1 protein, human Nuclear Receptor Co-Repressor 1 Nuclear Receptor Co-Repressor 2 Orphan Nuclear Receptors PPAR gamma Receptors, Cytoplasmic and Nuclear Receptors, Glucocorticoid Repressor Proteins
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Glass Christopher K
Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, GPL Room 217A, La Jolla, California 92093-0651, USA. [email protected]
Saijo Kaoru
References (78)
78 references, click to expand
  1. Traditional concepts and future avenues of glucocorticoid action in experimental autoimmune encephalomyelitis and multiple sclerosis therapy.
    Crit Rev Immunol. 2009;29(3):255-73 PMID: 19538138
  2. Altered subcellular distribution of MSK1 induced by glucocorticoids contributes to NF-kappaB inhibition.
    EMBO J. 2008 Jun 18;27(12):1682-93 PMID: 18511904
  3. A nuclear receptor corepressor-dependent pathway mediates suppression of cytokine-induced C-reactive protein gene expression by liver X receptor.
    Circ Res. 2006 Dec 8;99(12):e88-99 PMID: 17110595
  4. A transcriptional co-repressor that interacts with nuclear hormone receptors.
    Nature. 1995 Oct 5;377(6548):454-7 PMID: 7566127
  5. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1.
    Cell. 2005 Jul 15;122(1):33-43 PMID: 16009131
  6. The glucocorticoid receptor blocks P-TEFb recruitment by NFkappaB to effect promoter-specific transcriptional repression.
    Genes Dev. 2005 May 1;19(9):1116-27 PMID: 15879558
  7. The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity.
    J Exp Med. 2009 Sep 28;206(10):2079-89 PMID: 19737866
  8. Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice.
    Cell Metab. 2009 Nov;10(5):419-29 PMID: 19883619
  9. A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors.
    Cell. 2004 Feb 20;116(4):511-26 PMID: 14980219
  10. The nuclear orphan receptor NR2F6 suppresses lymphocyte activation and T helper 17-dependent autoimmunity.
    Immunity. 2008 Aug 15;29(2):205-16 PMID: 18701084
  11. The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: molecular mechanisms for gene repression.
    Endocr Rev. 2003 Aug;24(4):488-522 PMID: 12920152
  12. Defining requirements for heterodimerization between the retinoid X receptor and the orphan nuclear receptor Nurr1.
    J Biol Chem. 2002 Sep 20;277(38):35118-23 PMID: 12130634
  13. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR.
    Immunity. 2009 Aug 21;31(2):245-58 PMID: 19646905
  14. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma.
    Nature. 2005 Sep 29;437(7059):759-63 PMID: 16127449
  15. Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma.
    Mol Cell. 2007 Jan 12;25(1):57-70 PMID: 17218271
  16. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death.
    Cell. 2009 Apr 3;137(1):47-59 PMID: 19345186
  17. FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription.
    Cell. 2008 Mar 21;132(6):958-70 PMID: 18358809
  18. GPS2-dependent corepressor/SUMO pathways govern anti-inflammatory actions of LRH-1 and LXRbeta in the hepatic acute phase response.
    Genes Dev. 2010 Feb 15;24(4):381-95 PMID: 20159957
  19. Toll-like receptors and innate immunity.
    Nat Rev Immunol. 2001 Nov;1(2):135-45 PMID: 11905821
  20. The nuclear receptor superfamily: the second decade.
    Cell. 1995 Dec 15;83(6):835-9 PMID: 8521507
  21. Glucocorticoids and the innate immune system: crosstalk with the toll-like receptor signaling network.
    Mol Cell Endocrinol. 2007 Sep 15;275(1-2):30-42 PMID: 17576036
  22. Transcriptional regulatory networks in Th17 cell differentiation.
    Curr Opin Immunol. 2009 Apr;21(2):146-52 PMID: 19328669
  23. Estrogen down-regulation of the corepressor N-CoR: mechanism and implications for estrogen derepression of N-CoR-regulated genes.
    Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13153-7 PMID: 16141343
  24. One nucleotide in a kappaB site can determine cofactor specificity for NF-kappaB dimers.
    Cell. 2004 Aug 20;118(4):453-64 PMID: 15315758
  25. PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale.
    Genes Dev. 2008 Nov 1;22(21):2941-52 PMID: 18981473
  26. TLR4 links innate immunity and fatty acid-induced insulin resistance.
    J Clin Invest. 2006 Nov;116(11):3015-25 PMID: 17053832
  27. Toll-like receptors in systemic autoimmune disease.
    Nat Rev Immunol. 2006 Nov;6(11):823-35 PMID: 17063184
  28. Nuclear receptors and lipid physiology: opening the X-files.
    Science. 2001 Nov 30;294(5548):1866-70 PMID: 11729302
  29. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network.
    Cell. 2006 Aug 25;126(4):789-99 PMID: 16923397
  30. Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response.
    Genes Dev. 2006 Jun 1;20(11):1405-28 PMID: 16751179
  31. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor.
    Nature. 1995 Oct 5;377(6548):397-404 PMID: 7566114
  32. Genome-wide profiling of PPARgamma:RXR and RNA polymerase II occupancy reveals temporal activation of distinct metabolic pathways and changes in RXR dimer composition during adipogenesis.
    Genes Dev. 2008 Nov 1;22(21):2953-67 PMID: 18981474
  33. C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet.
    Diabetologia. 2007 Jun;50(6):1267-76 PMID: 17426960
  34. Cracking the coregulator codes.
    Curr Opin Cell Biol. 2008 Jun;20(3):310-5 PMID: 18499426
  35. Molecular determinants of crosstalk between nuclear receptors and toll-like receptors.
    Cell. 2005 Sep 9;122(5):707-21 PMID: 16143103
  36. Type I interferons (alpha/beta) in immunity and autoimmunity.
    Annu Rev Immunol. 2005;23:307-36 PMID: 15771573
  37. Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones.
    EMBO J. 2001 Nov 1;20(21):6071-83 PMID: 11689447
  38. Toll-like receptors.
    Curr Protoc Immunol. 2007 May;Chapter 14:Unit 14.12 PMID: 18432983
  39. A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation.
    Proc Natl Acad Sci U S A. 2004 Oct 5;101(40):14461-6 PMID: 15452344
  40. Heterodimerization between members of the Nur subfamily of orphan nuclear receptors as a novel mechanism for gene activation.
    Mol Cell Biol. 1999 Nov;19(11):7549-57 PMID: 10523643
  41. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.
    Immunity. 2008 Jan;28(1):29-39 PMID: 18164222
  42. Phosphorylation of serine 468 by GSK-3beta negatively regulates basal p65 NF-kappaB activity.
    J Biol Chem. 2004 Nov 26;279(48):49571-4 PMID: 15465828
  43. A Nuclear Receptor Atlas: macrophage activation.
    Mol Endocrinol. 2005 Oct;19(10):2466-77 PMID: 16051664
  44. Stimulus specificity of gene expression programs determined by temporal control of IKK activity.
    Science. 2005 Sep 16;309(5742):1857-61 PMID: 16166517
  45. MEKK1 plays a critical role in activating the transcription factor C/EBP-beta-dependent gene expression in response to IFN-gamma.
    Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):7945-50 PMID: 12048245
  46. SMRT and N-CoR corepressors are regulated by distinct kinase signaling pathways.
    J Biol Chem. 2004 Dec 24;279(52):54676-86 PMID: 15491994
  47. Cooperative NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory and anti-inflammatory signaling pathways.
    Genes Dev. 2009 Mar 15;23(6):681-93 PMID: 19299558
  48. Minireview: latest perspectives on antiinflammatory actions of glucocorticoids.
    Mol Endocrinol. 2009 Mar;23(3):281-91 PMID: 19095768
  49. Biological roles and mechanistic actions of co-repressor complexes.
    J Cell Sci. 2002 Feb 15;115(Pt 4):689-98 PMID: 11865025
  50. Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines.
    Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8381-6 PMID: 18550828
  51. Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity.
    Circ Res. 2007 Jun 8;100(11):1589-96 PMID: 17478729
  52. IL-17 and Th17 Cells.
    Annu Rev Immunol. 2009;27:485-517 PMID: 19132915
  53. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid.
    Science. 2007 Jul 13;317(5835):256-60 PMID: 17569825
  54. Combinatorial roles of nuclear receptors in inflammation and immunity.
    Nat Rev Immunol. 2006 Jan;6(1):44-55 PMID: 16493426
  55. SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron.
    Nature. 2007 Nov 15;450(7168):415-9 PMID: 17928865
  56. Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease.
    Cell Physiol Biochem. 2007;20(6):947-56 PMID: 17982277
  57. Toll-like receptor signalling.
    Nat Rev Immunol. 2004 Jul;4(7):499-511 PMID: 15229469
  58. Modulation of atherosclerosis in mice by Toll-like receptor 2.
    J Clin Invest. 2005 Nov;115(11):3149-56 PMID: 16211093
  59. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways.
    J Biol Chem. 2007 Nov 30;282(48):35279-92 PMID: 17916553
  60. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis.
    Proc Staff Meet Mayo Clin. 1949 Apr 13;24(8):181-97 PMID: 18118071
  61. Alternate surfaces of transcriptional coregulator GRIP1 function in different glucocorticoid receptor activation and repression contexts.
    Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16701-6 PMID: 12481024
  62. Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes.
    Mol Cell. 2009 Sep 24;35(6):806-17 PMID: 19782030
  63. Corticosteroids reduce IL-6 in ASM cells via up-regulation of MKP-1.
    Am J Respir Cell Mol Biol. 2008 Aug;39(2):208-17 PMID: 18314542
  64. A nuclear isoform of the focal adhesion LIM-domain protein Trip6 integrates activating and repressing signals at AP-1- and NF-kappaB-regulated promoters.
    Genes Dev. 2004 Oct 15;18(20):2518-28 PMID: 15489293
  65. Peripheral T cells are the therapeutic targets of glucocorticoids in experimental autoimmune encephalomyelitis.
    J Immunol. 2008 Jun 15;180(12):8434-43 PMID: 18523311
  66. Glucocorticoids in T cell development and function*.
    Annu Rev Immunol. 2000;18:309-45 PMID: 10837061
  67. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors.
    Nat Med. 2003 Feb;9(2):213-9 PMID: 12524534
  68. The SMRT corepressor is regulated by a MEK-1 kinase pathway: inhibition of corepressor function is associated with SMRT phosphorylation and nuclear export.
    Mol Cell Biol. 2000 Sep;20(17):6612-25 PMID: 10938135
  69. PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance.
    Nat Med. 2009 Nov;15(11):1266-72 PMID: 19838202
  70. A novel mitogen-activated protein kinase phosphatase-1 and glucocorticoid receptor (GR) interacting protein-1-dependent combinatorial mechanism of gene transrepression by GR.
    Mol Endocrinol. 2009 Jan;23(1):86-99 PMID: 18945810
  71. Restriction to Fos family members of Trip6-dependent coactivation and glucocorticoid receptor-dependent trans-repression of activator protein-1.
    Mol Endocrinol. 2008 Aug;22(8):1767-80 PMID: 18535250
  72. Transcriptional integration of TLR2 and TLR4 signaling at the NCoR derepression checkpoint.
    Mol Cell. 2009 Jul 10;35(1):48-57 PMID: 19595715
  73. PPARgamma-dependent regulation of human macrophages in phagocytosis of apoptotic cells.
    Eur J Immunol. 2007 May;37(5):1343-54 PMID: 17407194
  74. Toll-like receptor 4-dependent and -independent cytokine secretion induced by minimally oxidized low-density lipoprotein in macrophages.
    Arterioscler Thromb Vasc Biol. 2005 Jun;25(6):1213-9 PMID: 15718493
  75. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E.
    Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10679-84 PMID: 15249654
  76. Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance.
    Cell Metab. 2008 Jun;7(6):496-507 PMID: 18522831
  77. Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors.
    Nature. 2003 May 29;423(6939):555-60 PMID: 12774125
  78. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.
    Cell. 2006 Sep 22;126(6):1121-33 PMID: 16990136
Article Info
Journal
Nature reviews. Immunology
Abbr.
Nat Rev Immunol
ISSN
1474-1741
DOI
10.1038/nri2748
Email
[email protected]
Published
2010-05-00
Pages
365-76
Language
English
Region
England
NLM ID
101124169
Subset
IM
External Links
PubMed source DOI: 10.1038/nri2748 View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2