Skip to main content
SpringerLink
Log in

RORs in Autoimmune Disease

  • Chapter
  • First Online:
Sphingosine-1-Phosphate Signaling in Immunology and Infectious Diseases

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 378))

Abstract

The retinoic acid receptor-related orphan receptor (ROR) subfamily of nuclear receptors are transcription factors involved in the maintenance of circadian rhythm and are essential for proper immune function. The T cell-specific isoform, RORγt, is required for T helper 17 cells (TH17) development and it has been implicated in the pathogenesis of autoimmune diseases including multiple sclerosis and rheumatoid arthritis. Thus, pharmacological repression of RORγt may provide a strategy for therapeutic intervention in autoimmune disorders. This chapter provides a summary of the current status for target validation and development of new chemical entities targeting RORγt.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Alonzi T et al (1998) Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med 187(4):461–468

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Andre E et al (1998a) Disruption of retinoid-related orphan receptor beta changes circadian behavior, causes retinal degeneration and leads to vacillans phenotype in mice. EMBO J 17(14):3867–3877

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Andre E, Gawlas K, Becker-Andre M (1998b) A novel isoform of the orphan nuclear receptor RORbeta is specifically expressed in pineal gland and retina. Gene 216(2):277–283

    Article  CAS  PubMed  Google Scholar 

  • Barish GD et al (2005) A nuclear receptor atlas: macrophage activation. Mol Endocrinol 19(10):2466–2477

    Article  CAS  PubMed  Google Scholar 

  • Becker-Andre M, Andre E, DeLamarter JF (1993) Identification of nuclear receptor mRNAs by RT-PCR amplification of conserved zinc-finger motif sequences. Biochem Biophys Res Commun 194(3):1371–1379

    Article  CAS  PubMed  Google Scholar 

  • Bertolini DR et al (1986) Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature 319(6053):516–518

    Article  CAS  PubMed  Google Scholar 

  • Burris TP (2008) Nuclear hormone receptors for heme: REV-ERB alpha and REV-ERB beta are ligand-regulated components of the mammalian clock. Mol Endocrinol 22(7):1509–1520

    Article  CAS  PubMed  Google Scholar 

  • Chang MR et al (2014) Pharmacological repression of RORgamma is therapeutic in the collagen-induced arthritis experimental model. Arthritis Rheumatd 66(3):579--588

    Google Scholar 

  • Carlberg C et al (1994) RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers. Mol Endocrinol 8(6):757–770

    CAS  PubMed  Google Scholar 

  • Clinckemalie L et al (2012) The hinge region in androgen receptor control. Mol Cell Endocrinol 358(1):1–8

    CAS  PubMed  Google Scholar 

  • Dayer JM, Beutler B, Cerami A (1985) Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med 162(6):2163–2168

    Article  CAS  PubMed  Google Scholar 

  • Duerr RH et al (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314(5804):1461–1463

    Article  CAS  PubMed  Google Scholar 

  • Evans RM (1988) The steroid and thyroid hormone receptor superfamily. Science 240(4854):889–895

    Article  CAS  PubMed  Google Scholar 

  • Fossiez F et al (1996) T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med 183(6):2593–2603

    Article  CAS  PubMed  Google Scholar 

  • Fujiwara N, Kobayashi K (2005) Macrophages in inflammation. Curr Drug Targets Inflamm Allergy 4(3):281–286

    Article  CAS  PubMed  Google Scholar 

  • Gaffen SL (2008) An overview of IL-17 function and signaling. Cytokine 43(3):402–407

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Genovese MC et al (2010) LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I randomized, double-blind, placebo-controlled, proof-of-concept study. Arthritis Rheum 62(4):929–939

    Article  CAS  PubMed  Google Scholar 

  • Griffin PR et al (2011) Modulators of the retinoic acid receptor-related orphan receptors. The Scripps Research Institute. WO 2011115892

    Google Scholar 

  • Giguere V et al (1994) Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. Genes Dev 8(5):538–553

    Article  CAS  PubMed  Google Scholar 

  • Gu Y et al (2008) Interleukin 10 suppresses Th17 cytokines secreted by macrophages and T cells. Eur J Immunol 38(7):1807–1813

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hamilton BA et al (1996) Disruption of the nuclear hormone receptor RORalpha in staggerer mice. Nature 379(6567):736–739

    Article  CAS  PubMed  Google Scholar 

  • Heery DM et al (1997) A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387(6634):733–736

    Article  CAS  PubMed  Google Scholar 

  • Hirose T, Smith RJ, Jetten AM (1994) ROR gamma: the third member of ROR/RZR orphan receptor subfamily that is highly expressed in skeletal muscle. Biochem Biophys Res Commun 205(3):1976–1983

    Article  CAS  PubMed  Google Scholar 

  • Hot A, Miossec P (2011) Effects of interleukin (IL)-17A and IL-17F in human rheumatoid arthritis synoviocytes. Ann Rheum Dis 70(5):727–732

    Article  CAS  PubMed  Google Scholar 

  • Hu X, Lazar MA (1999) The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature 402(6757):93–96

    Article  CAS  PubMed  Google Scholar 

  • Ivanov II et al (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126(6):1121–1133

    Article  CAS  PubMed  Google Scholar 

  • Jetten AM (2009) Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl Recept Signal 7:e003

    PubMed Central  PubMed  Google Scholar 

  • Jetten AM, Kurebayashi S, Ueda E (2001) The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes. Prog Nucleic Acid Res Mol Biol 69:205–247

    Article  CAS  PubMed  Google Scholar 

  • Joosten LA et al (1999) IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation. J Immunol 163(9):5049–5055

    CAS  PubMed  Google Scholar 

  • Kamenecka TM et al (2013) Synthetic modulators of the retinoic acid receptor-related orphan receptors. Medchemcomm 4(5):764–776

    Article  CAS  Google Scholar 

  • Kishimoto T (2005) Interleukin-6: from basic science to medicine–40 years in immunology. Annu Rev Immunol 23:1–21

    Article  CAS  PubMed  Google Scholar 

  • Koenders MI et al (2005) Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1. Am J Pathol 167(1):141–149

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kolls JK, Linden A (2004) Interleukin-17 family members and inflammation. Immunity 21(4):467–476

    Article  CAS  PubMed  Google Scholar 

  • Korn T et al (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517

    Article  CAS  PubMed  Google Scholar 

  • Kotake S et al (1999) IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 103(9):1345–1352

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Krasowski MD, Reschly EJ, Ekins S (2008) Intrinsic disorder in nuclear hormone receptors. J Proteome Res 7(10):4359–4372

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kumar N et al (2010a) Campaign to identify novel modulators of the retinoic acid receptor-related orphan receptors (ROR). Probe Reports from the NIH Molecular Libraries Program

    Google Scholar 

  • Kumar N et al (2010) The benzenesulfoamide T0901317 [N-(2, 2, 2-trifluoroethyl)-N-[4-[2, 2, 2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethy l]phenyl]-benzenesulfonamide] is a novel retinoic acid receptor-related orphan receptor-alpha/gamma inverse agonist. Mol Pharmacol 77(2):228–236

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kumar N et al (2012) Identification of SR2211: a potent synthetic RORgamma-selective modulator. ACS Chem Biol 7(4):672–677

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lubberts E, Koenders MI, van den Berg WB (2005) The role of T-cell interleukin-17 in conducting destructive arthritis: lessons from animal models. Arthritis Res Ther 7(1):29–37

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Miossec P (2007) Interleukin-17 in fashion, at last: ten years after its description, its cellular source has been identified. Arthritis Rheum 56(7):2111–2115

    Article  CAS  PubMed  Google Scholar 

  • Moore JT, Collins JL, Pearce KH (2006) The nuclear receptor superfamily and drug discovery. Chem Med Chem 1(5):504–523

    Article  CAS  PubMed  Google Scholar 

  • Nair RP et al (2009) Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet 41(2):199–204

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Overington JP, Al-Lazikani B, Hopkins AL (2006) How many drug targets are there? Nat Rev Drug Discov 5(12):993–996

    CAS  PubMed  Google Scholar 

  • Park MC et al (2010) Liver X receptor agonist prevents the evolution of collagen-induced arthritis in mice. Rheumatol (Oxford) 49(5):882–890

    Article  CAS  Google Scholar 

  • Privalsky ML (2004) The role of corepressors in transcriptional regulation by nuclear hormone receptors. Annu Rev Physiol 66:315–360

    Article  CAS  PubMed  Google Scholar 

  • Raghuram S et al (2007) Identification of heme as the ligand for the orphan nuclear receptors REV-ERB alpha and REV-ERB beta. Nat Struct Mol Biol 14(12):1207–1213

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Smolen JS et al (1995) Validity and reliability of the twenty-eight-joint count for the assessment of rheumatoid arthritis activity. Arthritis Rheum 38(1):38–43

    Article  CAS  PubMed  Google Scholar 

  • Solt LA et al (2011) Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472(7344):491–494

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Solt LA et al (2012) Identification of a selective RORgamma ligand that suppresses T(H)17 cells and stimulates T regulatory cells. ACS Chem Biol 7(9):1515–1519

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Song C et al (2008) IL-17-producing alveolar macrophages mediate allergic lung inflammation related to asthma. J Immunol 181(9):6117–6124

    Article  CAS  PubMed  Google Scholar 

  • Spencer TE et al (1997) Steroid receptor coactivator-1 is a histone acetyltransferase. Nature 389(6647):194–198

    Article  CAS  PubMed  Google Scholar 

  • Stahl EA et al (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42(6):508–514

    Article  CAS  PubMed  Google Scholar 

  • Steinmayr M et al (1998) Staggerer phenotype in retinoid-related orphan receptor alpha-deficient mice. Proc Natl Acad Sci U S A 95(7):3960–3965

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sun Z et al (2000) Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science 288(5475):2369–2373

    Article  CAS  PubMed  Google Scholar 

  • Takemura S et al (2001) Lymphoid neogenesis in rheumatoid synovitis. J Immunol 167(2):1072–1080

    Article  CAS  PubMed  Google Scholar 

  • Tesmer LA et al (2008) Th17 cells in human disease. Immunol Rev 223:87–113

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Toy D et al (2006) Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J Immunol 177(1):36–39

    Article  CAS  PubMed  Google Scholar 

  • Tremblay GB et al (1999) Dominant activity of activation function 1 (AF-1) and differential stoichiometric requirements for AF-1 and -2 in the estrogen receptor alpha-beta heterodimeric complex. Mol Cell Biol 19(3):1919–1927

    CAS  PubMed Central  PubMed  Google Scholar 

  • van de Veerdonk FL et al (2011) The anti-CD20 antibody rituximab reduces the Th17 cell response. Arthritis Rheum 63(6):1507–1516

    Article  PubMed  Google Scholar 

  • van den Berg WB, Miossec P (2009) IL-17 as a future therapeutic target for rheumatoid arthritis. Nat Rev Rheumatol 5(10):549–553

    Article  PubMed  Google Scholar 

  • Wang Y et al (2010) Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands. J Biol Chem 285(7):5013–5025

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Warnmark A et al (2003) Activation functions 1 and 2 of nuclear receptors: molecular strategies for transcriptional activation. Mol Endocrinol 17(10):1901–1909

    Article  PubMed  Google Scholar 

  • Yang XO et al (2008) T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28(1):29–39

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yu Q et al (2004) IL-7 receptor signals inhibit expression of transcription factors TCF-1, LEF-1, and RORgammat: impact on thymocyte development. J Exp Med 200(6):797–803

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zwart W et al (2010) The hinge region of the human estrogen receptor determines functional synergy between AF-1 and AF-2 in the quantitative response to estradiol and tamoxifen. J Cell Sci 123(Pt 8):1253–1261

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL, 33458, USA

    Mi Ra Chang, Hugh Rosen & Patrick R. Griffin

Authors
  1. Mi Ra Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hugh Rosen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrick R. Griffin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrick R. Griffin .

Editor information

Editors and Affiliations

  1. Department of Immunology and Microbial Sciiences, The Scripps Research Institute, La Jolla, California, USA

    Michael B. A. Oldstone

  2. Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA

    Hugh Rosen

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Chang, M.R., Rosen, H., Griffin, P.R. (2014). RORs in Autoimmune Disease. In: Oldstone, M., Rosen, H. (eds) Sphingosine-1-Phosphate Signaling in Immunology and Infectious Diseases. Current Topics in Microbiology and Immunology, vol 378. Springer, Cham. https://doi.org/10.1007/978-3-319-05879-5_8

Download citation

Publish with us

Policies and ethics

Search

Navigation