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PMID: 18550828 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 105 ·No. 24 ·2008-06-17 ·Pages 8381-6

Doi Y, Oki S, Ozawa T, Hohjoh H, Miyake S, Yamamura T

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) mediated by Th17 and Th1 cells. DNA microarray analysis previously showed that NR4A2, an orphan nuclear receptor, is strongly up-regulated in the peripheral blood T cells of MS. Here, we report that NR4A2 plays a pivotal role for mediating cytokine production from pathogenic T cells. In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, NR4A2, was selectively up-regulated in the T cells isolated from the CNS. Strikingly, a forced expression of NR4A2 augmented promoter activities of IL-17 and IFN-gamma genes, leading to an excessive production of these cytokines. Conversely, treatment with siRNA for NR4A2, resulted in a significant reduction in the production of IL-17 and IFN-gamma. Furthermore, treatment with NR4A2 siRNA reduced the ability of encephalitogenic T cells to transfer EAE in recipient mice. Thus, NR4A2 is an essential transcription factor for triggering the inflammatory cascade of MS/EAE and may serve as a therapeutic target.

MeSH Terms
Animals Brain/immunology Cytokines/biosynthesis,genetics DNA-Binding Proteins/genetics,metabolism Encephalomyelitis, Autoimmune, Experimental/genetics,immunology,therapy Female Gene Silencing Interferon-gamma/biosynthesis,genetics Interleukin-17/biosynthesis,genetics Mice Multiple Sclerosis/genetics,immunology,therapy Nuclear Receptor Subfamily 4, Group A, Member 2 RNA, Small Interfering/genetics Retroviridae/genetics T-Lymphocytes/immunology Transcription Factors/genetics,metabolism Transduction, Genetic Up-Regulation
Chemicals
Cytokines DNA-Binding Proteins Interleukin-17 Nr4a2 protein, mouse Nuclear Receptor Subfamily 4, Group A, Member 2 RNA, Small Interfering Transcription Factors Interferon-gamma
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Doi Yoshimitsu
Departments of Immunology and Molecular Genetics, National Institute of Neuroscience, National Center of Neurology and Psychiatry,4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
Oki Shinji
Ozawa Tomoko
Hohjoh Hirohiko
Miyake Sachiko
Yamamura Takashi
References (39)
39 references, click to expand
  1. RORgamma t, a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells.
    Immunity. 1998 Dec;9(6):797-806 PMID: 9881970
  2. A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection.
    Immunity. 1995 Sep;3(3):273-82 PMID: 7552993
  3. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis.
    Nat Med. 2002 May;8(5):500-8 PMID: 11984595
  4. Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis.
    J Clin Invest. 2001 Sep;108(5):739-47 PMID: 11544280
  5. Invariant V(alpha)19i T cells regulate autoimmune inflammation.
    Nat Immunol. 2006 Sep;7(9):987-94 PMID: 16878136
  6. IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis.
    J Immunol. 1996 Oct 15;157(8):3223-7 PMID: 8871615
  7. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis.
    J Exp Med. 2004 Jul 5;200(1):79-87 PMID: 15238607
  8. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid.
    Science. 2007 Jul 13;317(5835):256-60 PMID: 17569825
  9. Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells.
    J Exp Med. 1996 Apr 1;183(4):1879-92 PMID: 8666944
  10. Microarray analysis identifies an aberrant expression of apoptosis and DNA damage-regulatory genes in multiple sclerosis.
    Neurobiol Dis. 2005 Apr;18(3):537-50 PMID: 15755681
  11. Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis.
    Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10132-7 PMID: 10963675
  12. T-lymphocyte entry into the central nervous system.
    J Neurosci Res. 1991 Feb;28(2):254-60 PMID: 2033653
  13. The NR4A subgroup: immediate early response genes with pleiotropic physiological roles.
    Nucl Recept Signal. 2006;4:e002 PMID: 16604165
  14. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand.
    Nat Med. 2000 Oct;6(10):1167-75 PMID: 11017150
  15. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis.
    Am J Pathol. 2008 Jan;172(1):146-55 PMID: 18156204
  16. Mutations in NR4A2 associated with familial Parkinson disease.
    Nat Genet. 2003 Jan;33(1):85-9 PMID: 12496759
  17. Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells.
    Nat Immunol. 2007 Jan;8(1):74-83 PMID: 17143274
  18. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.
    J Exp Med. 2005 Jan 17;201(2):233-40 PMID: 15657292
  19. Dopamine neuron agenesis in Nurr1-deficient mice.
    Science. 1997 Apr 11;276(5310):248-50 PMID: 9092472
  20. Kinetics and organ distribution of IL-17-producing CD4 cells in proteolipid protein 139-151 peptide-induced experimental autoimmune encephalomyelitis of SJL mice.
    J Immunol. 2007 Feb 1;178(3):1372-8 PMID: 17237384
  21. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system.
    Neurology. 1987 Jul;37(7):1097-102 PMID: 3110648
  22. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research.
    Brain. 2006 Aug;129(Pt 8):1953-71 PMID: 16632554
  23. Cytokine flow cytometry differentiates the clinical status of multiple sclerosis (MS) patients.
    Clin Exp Immunol. 1999 Mar;115(3):521-5 PMID: 10193428
  24. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.
    Nature. 2003 Feb 13;421(6924):744-8 PMID: 12610626
  25. T cell gene expression profiling identifies distinct subgroups of Japanese multiple sclerosis patients.
    J Neuroimmunol. 2006 May;174(1-2):108-18 PMID: 16564577
  26. Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas.
    Nature. 1994 Jan 20;367(6460):277-81 PMID: 8121493
  27. Immunology of multiple sclerosis.
    Annu Rev Immunol. 2005;23:683-747 PMID: 15771584
  28. Myelin basic protein-specific T lymphocyte repertoire in multiple sclerosis. Complexity of the response and dominance of nested epitopes due to recruitment of multiple T cell clones.
    J Clin Invest. 1993 Dec;92(6):2633-43 PMID: 7504690
  29. T(H)-17 cells in the circle of immunity and autoimmunity.
    Nat Immunol. 2007 Apr;8(4):345-50 PMID: 17375096
  30. Th17: the third member of the effector T cell trilogy.
    Curr Opin Immunol. 2007 Dec;19(6):652-7 PMID: 17766098
  31. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12.
    J Clin Invest. 2002 Aug;110(4):493-7 PMID: 12189243
  32. Functional redundancy of the Nur77 and Nor-1 orphan steroid receptors in T-cell apoptosis.
    EMBO J. 1997 Apr 15;16(8):1865-75 PMID: 9155013
  33. An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells.
    Nat Immunol. 2004 Jan;5(1):64-73 PMID: 14691482
  34. Gene microarray analysis of multiple sclerosis lesions.
    Trends Mol Med. 2003 Dec;9(12):535-41 PMID: 14659468
  35. Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion.
    J Exp Med. 2005 Jun 6;201(11):1805-14 PMID: 15939794
  36. The clinical implication and molecular mechanism of preferential IL-4 production by modified glycolipid-stimulated NKT cells.
    J Clin Invest. 2004 Jun;113(11):1631-40 PMID: 15173890
  37. Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-beta 2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system.
    J Immunol. 2003 Feb 15;170(4):2153-60 PMID: 12574388
  38. Apoptotic signals delivered through the T-cell receptor of a T-cell hybrid require the immediate-early gene nur77.
    Nature. 1994 Jan 20;367(6460):281-4 PMID: 8121494
  39. 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
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0803454105
Published
2008-06-17
Epub
2008-00-11
Pages
8381-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2426110
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0803454105 PMC Full Text View journal details
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