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Combinatorial roles of nuclear receptors in inflammation and immunity

Key Points

  • Members of the nuclear-receptor superfamily are ligand-dependent transcription factors that regulate diverse aspects of development, homeostasis, reproduction and immunity.

  • Nuclear receptors positively regulate gene expression by binding to response elements in target genes and recruiting (in a ligand-dependent manner) diverse co-activator complexes that modify chromatin and recruit core transcription factors.

  • Active repression by unliganded nuclear receptors is mediated by recruitment of co-repressor complexes. A well defined co-repressor complex consists of the nuclear-receptor co-repressor (NCoR) or the related factor silencing mediator of retinoic-acid and thyroid-hormone receptor (SMRT), histone deacetylase 3 (HDAC3), transducin-β-like 1 (TBL1), TBL1-related 1 (TBLR1), and G-protein-pathway suppressor 2 (GPS2).

  • Many inflammatory-response genes are occupied in the basal state by NCoR or SMRT co-repressor complexes that are required to maintain these genes in a repressed state in the absence of stimulus.

  • A conserved ubiquitylation-dependent molecular mechanism is required for both ligand-dependent exchange of NCoR or SMRT co-repressor complexes for co-activators on nuclear-receptor target genes and for signal-dependent exchange of these complexes on subsets of activator protein 1 (AP1) and nuclear factor-κB (NF-κB) target genes.

  • Several ligand-activated nuclear receptors, including the glucocorticoid receptor, peroxisome-proliferator-activated receptor-γ (PPARγ) and liver X receptors (LXRs), antagonize the actions of signal-dependent transcription factors that include AP1 and NF-κB. This activity, referred to as transrepression, accounts for many of the anti-inflammatory effects of glucocorticoid-receptor, LXR and PPARγ agonists.

  • Glucocorticoid-receptor, LXR and PPARγ agonists repress inflammatory responses in a signal-, promoter-, and receptor-specific manner through the use of multiple, receptor-specific mechanisms. These activities enable nuclear receptors to function in a combinatorial manner to regulate the evolution of innate and acquired immune responses

  • Signal- and promoter-specific transrepression of inflammatory-response genes by the glucocorticoid receptor can be achieved by targeting interferon-regulatory factor 3 (IRF3)–NF-κB complexes. Promoter-specific transrepression of inflammatory-response genes by PPARγ can be achieved by preventing the signal-dependent clearance of NCoR complexes

  • LXRs protect macrophages from bacterial-induced apoptosis and are required for normal immunity to Listeria monocytogenes.

  • It might be possible to develop new classes of small molecules for treatment of chronic inflammatory diseases by exploiting distinct, receptor-specific mechanisms for repression of signal-dependent gene expression.

Abstract

Members of the nuclear-receptor superfamily have well-documented regulatory effects on inflammatory processes. Recent work has highlighted the roles of peroxisome-proliferator-activated receptors (PPARs) and liver X receptors (LXRs) in controlling metabolic and inflammatory programmes of gene expression in macrophages and lymphocytes. Here, we describe recent studies that extend our understanding of how these nuclear receptors, through their interactions with transcription factors and other cell-signalling systems, have important regulatory roles in innate and adaptive immunity. We suggest that by using receptor-specific mechanisms, PPARs and LXRs function in a combinatorial manner with the glucocorticoid receptor to integrate local and systemic responses to inflammation.

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Figure 1: Domain structure of nuclear receptors.
Figure 2: Mechanisms of DNA binding and transcriptional activation.
Figure 3: Transcriptional activities of nuclear receptors.
Figure 4: Derepression as a prerequisite to activation of nuclear-receptor and inflammatory-response genes.
Figure 5: Models of promoter-specific and signal-specific repression of inflammatory response genes by PPARγ and the glucocorticoid receptor.
Figure 6: Model for how PPARγ and the glucocorticoid receptor could function to integrate local and systemic signals to counter-regulate inflammatory responses.

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References

  1. Evans, R. M. The steroid and thyroid hormone receptor superfamily. Science 240, 889–895 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Chawla, A., Repa, J., Evans, R. & Mangelsdorf, D. Nuclear receptors and lipid physiology: opening the X-files. Science 294, 1866–1870 (2001).

    CAS  PubMed  Google Scholar 

  3. Kastner, P., Mark, M. & Chambon, P. Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83, 859–869 (1995).

    CAS  PubMed  Google Scholar 

  4. Mangelsdorf, D. J. et al. The nuclear receptor superfamily: the second decade. Cell 83, 835–839 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kliewer, S. A., Umesono, K., Mangelsdorf, D. J. & Evans, R. M. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling. Nature 355, 446–449 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Yu, V. C. et al. RXRβ: a coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements. Cell 67, 1251–1266 (1991).

    CAS  PubMed  Google Scholar 

  7. Näär, A. M. et al. The orientation and spacing of core DNA-binding motifs dictate selective transcriptional responses to three nuclear receptors. Cell 65, 1267–1279 (1991).

    PubMed  Google Scholar 

  8. Umesono, K. & Evans, R. M. Determinants of target gene specificity for steroid/thyroid hormone receptors. Cell 57, 1139–1146 (1989).

    CAS  PubMed  Google Scholar 

  9. Umesono, K., Murakami, K. K., Thompson, C. C. & Evans, R. M. Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell 65, 1255–1266 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Bourguet, W., Ruff, M., Chambon, P., Gronemeyer, H. & Moras, D. Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-α. Nature 375, 377–382 (1995).

    CAS  PubMed  Google Scholar 

  11. Moras, D. & Gronemeyer, H. The nuclear receptor ligand-binding domain: structure and function. Curr. Opin. Cell. Biol. 10, 384–391 (1998).

    CAS  PubMed  Google Scholar 

  12. Renaud, J. -P. et al. Crystal structure of the RAR-γ ligand-binding domain bound to all-trans retinoic acid. Nature 378, 681–689 (1995).

    CAS  PubMed  Google Scholar 

  13. Wagner, R. L. et al. A structural role for hormone in the thyroid hormone receptor. Nature 378, 690–697 (1995).

    CAS  PubMed  Google Scholar 

  14. Heery, D. M., Kalkhoven, E., Hoare, S. & Parker, M. G. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387, 733–736 (1997).

    CAS  PubMed  Google Scholar 

  15. Torchia, J. et al. The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387, 677–684 (1997).

    CAS  PubMed  Google Scholar 

  16. Ding, X. F. et al. Nuclear receptor-binding sites of coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1): multiple motifs with different binding specificities. Mol. Endocrinol. 12, 302–313 (1998).

    CAS  PubMed  Google Scholar 

  17. Nolte, R. T. et al. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ. Nature 395, 137–143 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Shiau, A. K. et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95, 927–937 (1998).

    CAS  PubMed  Google Scholar 

  19. Darimont, B. D. et al. Structure and specificity of nuclear receptor–coactivator interactions. Genes Dev. 12, 3343–3356 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen, J. D. & Evans, R. M. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377, 454–457 (1995).

    CAS  PubMed  Google Scholar 

  21. Horlein, A. J. et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377, 397–404 (1995).

    CAS  PubMed  Google Scholar 

  22. Hu, X. & Lazar, M. The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature 402, 93–96 (1999).

    CAS  PubMed  Google Scholar 

  23. Perissi, V. et al. Molecular determinants of nuclear receptor–corepressor interaction. Genes Dev. 13, 3198–3208 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Webb, P. et al. The nuclear receptor corepressor (N-CoR) contains three isoleucine motifs (I/LXXII) that serve as receptor interaction domains (IDs). Mol. Endocrinol. 14, 1976–1985 (2000).

    CAS  PubMed  Google Scholar 

  25. Xu, H. E. et al. Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARα. Nature 415, 813–817 (2002).

    CAS  PubMed  Google Scholar 

  26. Brzozowski, A. M. et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389, 753–758 (1997).

    CAS  PubMed  Google Scholar 

  27. Kliewer, S. A. et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ. Proc. Natl Acad. Sci. USA 94, 4318–4323 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Forman, B. M., Chen, J. & Evans, R. M. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ. Proc. Natl Acad. Sci. USA 94, 4312–4317 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Forman, B. M. et al. 15-Deoxy-Δ12, 14- prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ. Cell 83, 803–812 (1995).

    CAS  PubMed  Google Scholar 

  30. Kliewer, S. A. et al. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptorγ and promotes adipocyte differentiation. Cell 83, 813–819 (1995).

    CAS  PubMed  Google Scholar 

  31. Nagy, L., Tontonoz, P., Alvarez, J. G. A., Chen, H. & Evans, R. M. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARγ. Cell 93, 229–240 (1998).

    CAS  PubMed  Google Scholar 

  32. Janowski, B. A., Willy, P. J., Devi, T. R., Falck, J. R. & Mangelsdorf, D. J. An oxysterol signalling pathway mediated by the nuclear receptor LXRα. Nature 383, 728–731 (1996).

    CAS  PubMed  Google Scholar 

  33. Janowski, B. A. et al. Structural requirements of ligands for the oxysterol liver X receptors LXRα and LXRβ. Proc. Natl Acad. Sci. USA 96, 266–271 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Lehmann, J. M. et al. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J. Biol. Chem. 272, 3137–3140 (1997).

    CAS  PubMed  Google Scholar 

  35. Glass, C. K. & Rosenfeld, M. G. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 14, 121–141 (2000).

    CAS  PubMed  Google Scholar 

  36. McKenna, N. J. & O'Malley, B. W. Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108, 465–474 (2002).

    CAS  PubMed  Google Scholar 

  37. Smith, C. L. & O'Malley, B. W. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr. Rev. 25, 45–71 (2004).

    CAS  PubMed  Google Scholar 

  38. Lee, D. Y., Teyssier, C., Strahl, B. D. & Stallcup, M. R. Role of protein methylation in regulation of transcription. Endocr. Rev. 26, 147–170 (2005).

    CAS  PubMed  Google Scholar 

  39. Spiegelman, B. M. & Heinrich, R. Biological control through regulated transcriptional coactivators. Cell 119, 157–167 (2004).

    CAS  PubMed  Google Scholar 

  40. Damm, K., Thompson, C. C. & Evans, R. M. Protein encoded by v-erbA functions as a thyroid-hormone antagonist. Nature 339, 593–597 (1989).

    CAS  PubMed  Google Scholar 

  41. Sap, J., Munoz, A., Schmitt, J., Stunnenberg, H. & Vennstrom, B. Repression of transcription mediated at a thyroid hormone response element by the v-erb-A oncogene product. Nature 340, 242–244 (1989).

    CAS  PubMed  Google Scholar 

  42. Zhang, J., Kalkum, M., Chait, B. T. & Roeder, R. G. The N-CoR–HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. Mol. Cell 9, 611–623 (2002).

    CAS  PubMed  Google Scholar 

  43. Li, J. et al. Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J. 19, 4342–4350 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Guenther, M., Lane, W., Fischle, W., Verdin, E. & Lazar, M. A Core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness. Genes Dev. 14, 1048–1057 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Yoon, H. G. et al. Purification and functional characterization of the human N-CoR complex: the roles of HDAC3, TBL1 and TBLR1. EMBO J. 22, 1336–1346 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Perissi, V., Aggarwal, A., Glass, C. K., Rose, D. W. & Rosenfeld, M. G. A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors. Cell 116, 511–526 (2004). This paper reports that transcriptional activation mediated by ligand-bound nuclear receptors requires the actions of TBL1 and TBLR1. TBLR1 is shown to function as a specific adaptor for the recruitment of the ubiquitin-conjugating–19S-proteasome complex required for the exchange of the nuclear-receptor co-repressors NCoR or SMRT for co-activators.

    CAS  PubMed  Google Scholar 

  47. Helmberg, A., Auphan, N., Caelles, C. & Karin, M. Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor. EMBO J. 14, 452–460 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Jonat, C., Rahmsdorf, H. J., Park, K. K., Ponta, H. & Herrlich, P. Anti-tumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell 62, 1189–1204 (1990).

    CAS  PubMed  Google Scholar 

  49. Ray, A. & Prefontaine, K. E. Physical association and function antagonism between the p65 subunit of transcription factor NF-κB and the glucocorticoid receptor. Proc. Natl Acad. Sci. USA 91, 752–756 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Schule, R. et al. Retinoic acid is a negative regulator of AP-1-responsive genes. Proc. Natl Acad. Sci. USA 88, 6092–6096 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Yang-Yen, H. F. et al. Transcriptional interference between c-Jun and the glucocorticoid receptor: mutual inhibition of DNA binding due to direct protein-protein interaction. Cell 62, 1205–1215 (1990).

    CAS  PubMed  Google Scholar 

  52. Scheinman, R. I., Cogswell, P. C., Lofquist, A. K. & Baldwin, A. S. J. Role of transcriptional activation of IκBα in mediation of immunosuppression by glucocorticoids. Science 270, 283–286 (1995).

    CAS  PubMed  Google Scholar 

  53. Auphan, N., DiDonato, J. A., Rosette, C., Helmberg, A. & Karin, M. Immunosuppression by glucocorticoids: inhibition of NF-κB activity through induction of IκB synthesis. Science 270, 286–290 (1995).

    CAS  PubMed  Google Scholar 

  54. Caelles, C., Gonzales-Sancho, J. M. & Munoz, A. Nuclear hormone receptor antagonism with AP-1 by inhibition of the JNK pathway. Genes Dev. 11, 3351–3364 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Kamei, Y. et al. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85, 403–414 (1996).

    CAS  PubMed  Google Scholar 

  56. Sheppard, K. A. et al. Nuclear integration of glucocorticoid receptor and nuclear factor-κB signaling by CREB-binding protein and steroid receptor coactivator-1. J. Biol. Chem. 273, 29291–29294 (1998).

    CAS  PubMed  Google Scholar 

  57. Scheinman, R. I., Gualberto, A., Jewell, C. M., Cidlowski, J. A. & Baldwin, A. S. Jr. Characterization of mechanisms involved in transrepression of NF-κB activated glucocorticoid receptors. Mol. Cell. Biol. 15, 943–953 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Luecke, H. F. & Yamamoto, K. R. The glucocorticoid receptor blocks P-TEFb recruitment by NFκB to effect promoter-specific transcriptional repression. Genes Dev. 19, 1116–1127 (2005). This paper reports that alternative co-activator requirements at two NF-κB-responsive genes accounts for their differential regulation by glucocorticoid receptor.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. De Bosscher, K. et al. Glucocorticoids repress NF-κB-driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell. Proc. Natl Acad. Sci. USA 97, 3919–3924 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Nissen, R. M. & Yamamoto, K. R. The glucocorticoid receptor inhibits NF-κB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes Dev. 14, 2314–2329 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. De Bosscher, K., Vanden Berghe, W. & Haegeman, G. The interplay between the glucocorticoid receptor and nuclear factor-κB or activator protein-1: molecular mechanisms for gene repression. Endocr. Rev. 24, 488–522 (2003).

    CAS  PubMed  Google Scholar 

  62. Galon, J. et al. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J. 16, 61–71 (2002).

    CAS  PubMed  Google Scholar 

  63. Joseph, S. B., Castrillo, A., Laffitte, B. A., Mangelsdorf, D. J. & Tontonoz, P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nature Med. 9, 213–219 (2003). This paper is the first to report that LXRs and their ligands are negative regulators of macrophage inflammatory gene expression.

    CAS  PubMed  Google Scholar 

  64. Welch, J. S., Ricote, M., Akiyama, T. E., Gonzalez, F. J. & Glass, C. K. PPARγ and PPARδ negatively regulate specific subsets of lipopolysaccharide and IFNγ target genes in macrophages. Proc. Natl Acad. Sci. USA 100, 6712–6717 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Ogawa, S. et al. Molecular determinants of crosstalk between nuclear receptors and Toll-like receptors. Cell 122, 707–21 (2005). This paper reports a genome-wide analysis of counter-regulation of TLR signalling by nuclear receptors. Glucocorticoid receptor, PPARγ and LXRs were shown to repress TLR signalling in a receptor-, promoter- and signal-specific manner.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Lee, S. K., Kim, J. H., Lee, Y. C., Cheong, J. & Lee, J. W. Silencing mediator of retinoic acid and thyroid hormone receptors, as a novel transcriptional corepressor molecule of activating protein-1, nuclear factor-κB, and serum response factor. J. Biol. Chem. 275, 12470–12474 (2000).

    CAS  PubMed  Google Scholar 

  67. Ogawa, S. et al. A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation. Proc. Natl Acad. Sci. USA 101, 14461–14466 (2004). This paper reports a general role for NCoR as a co-repressor of subsets of inflammatory response genes in macrophages. Molecular analysis of AP1 target genes showed an essential role for JUN in NCoR recruitment.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Hoberg, J. E., Yeung, F. & Mayo, M. W. SMRT derepression by the IκB kinase α; A prerequisite to NF-κB transcription and survival. Mol. Cell 16, 245–255 (2004). This paper reports that NF-κB transcription requires IKKα to phosphorylate SMRT on chromatin, stimulating the proteasome-dependent exchange of co-repressor for co-activator complexes.

    CAS  PubMed  Google Scholar 

  69. Kelly, D. et al. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPARγ and RelA. Nature Immunol. 5, 104–112 (2004). This paper describes an anti-inflammatory mechanism, activated by non-pathogenic bacteria, that selectively antagonizes NF-κB in gut epithelial cells. Bacteroides thetaiotaomicron is shown to target transcriptionally active p65, increasing its nuclear export in a PPARγ-dependent manner.

    CAS  Google Scholar 

  70. Syrovets, T., Schule, A., Jendrach, M., Buchele, B. & Simmet, T. Ciglitazone inhibits plasmin-induced proinflammatory monocyte activation via modulation of p38 MAP kinase activity. Thromb. Haemost. 88, 274–281 (2002).

    CAS  PubMed  Google Scholar 

  71. Lee, C. H. et al. Transcriptional repression of atherogenic inflammation: modulation by PPARδ. Science 302, 453–457 (2003). This paper reports a pro-inflammatory role for unliganded PPARδ and an anti-inflammatory role for ligand-bound PPARγ in the macrophage.

    CAS  PubMed  Google Scholar 

  72. Delerive, P. et al. Peroxisome proliferator-activated receptor α negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-κB and AP-1. J. Biol. Chem. 274, 32048–53204 (1999).

    CAS  PubMed  Google Scholar 

  73. Pascual, G. et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPARγ. Nature 437, 759–763 (2005). This paper reports the identification of a sumoylation- and NCoR-dependent pathway by which PPARγ represses the transcriptional activation of inflammatory-response genes in macrophages.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Leung, T. H., Hoffmann, A. & Baltimore, D. One nucleotide in a κB site can determine cofactor specificity for NF-κB dimers. Cell 118, 453–464 (2004). Using lentivirus-based methodology, this paper shows that in genes with two NF-κB-binding sites, both sites are required for activity and they can function together as a module to regulate gene activation. The specific NF-κB sequence further dictates the co-activator requirements for gene activation, indicating a direct role for the κB element as an allosteric regulator of NF-κB.

    CAS  PubMed  Google Scholar 

  75. Schimmer, B. & Parker, K., in Goodman and Gilman's Pharmacological Basis of Therapeutics (eds Hardman, J. G. & Limbird, L. E.) (McGraw Hill, New York, 1996).

    Google Scholar 

  76. Reichardt, H. M. et al. Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor. EMBO J. 20, 7168–7173 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Reichardt, H. M. et al. DNA binding of the glucocorticoid receptor is not essential for survival. Cell 93, 531–541 (1998).

    CAS  PubMed  Google Scholar 

  78. McKay, L. I. & Cidlowski, J. A. Molecular control of immune/inflammatory responses: interactions between nuclear factor-κB and steroid receptor-signaling pathways. Endocr. Rev. 20, 435–459 (1999).

    CAS  PubMed  Google Scholar 

  79. Adcock, I. M. & Barnes, P. J. Ligand-induced differentiation of glucocorticoid receptor (GR) trans-repression and transactivation. Biochem. Soc. Trans. 24, 267S (1996).

    CAS  PubMed  Google Scholar 

  80. Joyce, D. A., Steer, J. H. & Abraham, L. J. Glucocorticoid modulation of human monocyte/macrophage function: control of TNF-α secretion. Inflamm. Res. 46, 447–451 (1997).

    CAS  PubMed  Google Scholar 

  81. Almawi, W. Y., Beyhum, H. N., Rahme, A. A. & Rieder, M. J. Regulation of cytokine and cytokine receptor expression by glucocorticoids. J. Leukoc. Biol. 60, 563–572 (1996).

    CAS  PubMed  Google Scholar 

  82. Kleinert, H., Euchenhofer, C., Ihrig-Biedert, I. & Forstermann, U. Glucocorticoids inhibit the induction of nitric oxide synthase II by down-regulating cytokine-induced activity of transcription factor nuclear factor-κB. Mol. Pharmacol. 49, 15–21 (1996).

    CAS  PubMed  Google Scholar 

  83. Tanaka, J. et al. Glucocorticoid- and mineralocorticoid receptors in microgial cells: the two receptors mediate differential effects of corticosteroids. Glia 20, 523–537 (1997).

    CAS  Google Scholar 

  84. Koehler, L., Hass, R., DeWitt, D. L., Resch, K. & Goppelt-Struebe, M. Glucocorticoid-induced reduction of prostanoid synthesis in TPA- differentiated U937 cells is mainly due to a reduced cyclooxygenase activity. Biochem. Pharmacol. 40, 1307–1316 (1990).

    CAS  PubMed  Google Scholar 

  85. Lund, J., Sato, A., Akira, S., Medzhitov, R. & Iwasaki, A. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J. Exp. Med. 198, 513–520 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Krug, A. et al. Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9. Blood 103, 1433–1437 (2004).

    CAS  PubMed  Google Scholar 

  87. Ricote, M., Li, A. C., Willson, T. M., Kelly, C. J. & Glass, C. K. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature 391, 79–82 (1998).

    CAS  PubMed  Google Scholar 

  88. Jiang, C., Ting, A. T. & Seed, B. PPARγ agonists inhibit production of monocyte inflammatory cytokines. Nature 391, 82–86 (1998).

    CAS  PubMed  Google Scholar 

  89. Chinetti, G. et al. Activation of proliferator-activated receptors α and γ induces apoptosis of human monocyte-derived macrophages. J. Biol. Chem. 273, 25573–25580 (1998).

    CAS  PubMed  Google Scholar 

  90. Jones, D. C., Ding, X. & Daynes, R. A. Nuclear receptor peroxisome proliferator-activated receptor α (PPARα) is expressed in resting murine lymphocytes. The PPARα in T and B lymphocytes is both transactivation and transrepression competent. J. Biol. Chem. 277, 6838–6845 (2002).

    CAS  PubMed  Google Scholar 

  91. Cunard, R. et al. Regulation of cytokine expression by ligands of peroxisome proliferator activated receptors. J. Immunol. 168, 2795–2802 (2002).

    CAS  PubMed  Google Scholar 

  92. Clark, R. B. et al. The nuclear receptor PPARγ and immunoregulation: PPARγ mediates inhibition of helper T cell responses. J. Immunol. 164, 1364–1371 (2000).

    CAS  PubMed  Google Scholar 

  93. Setoguchi, K. et al. Peroxisome proliferator-activated receptor-γ haploinsufficiency enhances B cell proliferative responses and exacerbates experimentally induced arthritis. J. Clin. Invest. 108, 1667–1675 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Gosset, P. et al. Peroxisome proliferator-activated receptor γ activators affect the maturation of human monocyte-derived dendritic cells. Eur. J. Immunol. 31, 2857–2865 (2001).

    CAS  PubMed  Google Scholar 

  95. Faveeuw, C. et al. Peroxisome proliferator-activated receptor-γ activators inhibit interleukin-12 production in murine dendritic cells. FEBS Lett. 486, 261–266 (2000).

    CAS  PubMed  Google Scholar 

  96. Szatmari, I. et al. Activation of PPARγ specifies a dendritic cell subtype capable of enhanced induction of iNKT cell expansion. Immunity 21, 95–106 (2004).

    CAS  PubMed  Google Scholar 

  97. Delerive, P. et al. Peroxisome proliferator-activated receptor activators inhibit thrombin- induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circ. Res. 85, 394–402 (1999).

    CAS  PubMed  Google Scholar 

  98. Jackson, S. M. et al. Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction. Arterioscler. Thromb. Vasc. Biol. 19, 2094–2104 (1999).

    CAS  PubMed  Google Scholar 

  99. Marx, N., Sukhova, G. K., Collins, T., Libby, P. & Plutzky, J. PPARα activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation 99, 3125–3131 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Devchand, P. R. et al. The PPARα-leukotriene B4 pathway to inflammation control. Nature 384, 39–43 (1996).

    CAS  PubMed  Google Scholar 

  101. Staels, B. et al. Activation of human aortic smooth-muscle cells is inhibited by PPARα but not by PPARγ activators. Nature 393, 790–793 (1998).

    CAS  PubMed  Google Scholar 

  102. Castrillo, A. & Tontonoz, P. PPARs in atherosclerosis: the clot thickens. J. Clin. Invest. 114, 1538–1540 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Valledor, A. F. & Ricote, M. Nuclear receptor signaling in macrophages. Biochem. Pharmacol. 67, 201–212 (2004).

    CAS  PubMed  Google Scholar 

  104. Daynes, R. A. & Jones, D. C. Emerging roles of PPARs in inflammation and immunity. Nature Rev. Immunol. 2, 748–759 (2002).

    CAS  Google Scholar 

  105. Genolet, R., Wahli, W. & Michalik, L. PPARs as drug targets to modulate inflammatory responses? Curr. Drug Targets Inflamm. Allergy 3, 361–375 (2004).

    CAS  PubMed  Google Scholar 

  106. Straus, D. S. et al. 15-deoxy-Δ12, 14-prostaglandin J2 inhibits multiple steps in the NF-κB signaling pathway. Proc. Natl Acad. Sci. USA 97, 4844–4849 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Rossi, A. et al. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase. Nature 403, 103–108 (2000).

    CAS  PubMed  Google Scholar 

  108. Peet, D. J., Janowski, B. A. & Mangelsdorf, D. J. The LXRs: a new class of oxysterol receptors. Curr. Opin. Genet. Dev. 8, 571–575 (1998).

    CAS  PubMed  Google Scholar 

  109. Venkateswaran, A. et al. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXRα. Proc. Natl Acad. Sci. USA 97, 12097–12102 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Laffitte, B. A. et al. LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc. Natl Acad. Sci. USA 98, 507–512 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Joseph, S. B. et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc. Natl Acad. Sci. USA 99, 7604–7609 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Tangirala, R. K. et al. Identification of macrophage liver X receptors as inhibitors of atherosclerosis. Proc. Natl Acad. Sci. USA 99, 11896–11901 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Castrillo, A., Joseph, S. B., Marathe, C., Mangelsdorf, D. J. & Tontonoz, P. Liver X receptor-dependent repression of matrix metalloproteinase-9 expression in macrophages. J. Biol. Chem. 278, 10443–10449 (2003).

    CAS  PubMed  Google Scholar 

  114. Valledor, A. F. et al. Activation of liver X receptors and retinoid X receptors prevents bacterial-induced macrophage apoptosis. Proc. Natl Acad. Sci. USA 101, 17813–17818 (2004). This paper reports that activation of LXRs and RXRs protect macrophages from apoptosis caused by infection with B. anthracis, E. coli or S. typhimurium.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Joseph, S. B. et al. LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell 119, 299–309 (2004). This paper reports that mice lacking LXRs are highly susceptible to infection with the intracellular bacterium L. monocytogenes , because of increased macrophage apoptosis.

    CAS  PubMed  Google Scholar 

  116. Castrillo, A. et al. Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Mol. Cell 12, 805–816 (2003). This paper provides evidence that microbial pathogens interfere with macrophage cholesterol metabolism through inhibition of the LXR signaling pathway. Activation of TLR3 or TLR4 blocked the induction of LXR target genes in cultured macrophages, as well as in aortic tissue in vivo.

    CAS  PubMed  Google Scholar 

  117. Chen, Z. et al. Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL. Arterioscler. Thromb. Vasc. Biol. 21, 372–377 (2001).

    CAS  PubMed  Google Scholar 

  118. Claudel, T. et al. Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor. Proc. Natl Acad. Sci. USA 98, 2610–2615 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Collins, A. R. et al. Troglitazone inhibits formation of early atherosclerotic lesions in diabetic and nondiabetic low density lipoprotein receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 21, 365–371 (2001).

    CAS  PubMed  Google Scholar 

  120. Li, A. C. et al. Differential inhibition of macrophage foam cell formation and atherosclerosis in mice by PPAR α, β/δ, and γ. J. Clin. Invest. 114, 1564–1576 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Li, A. et al. Peroxisome proliferator-activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J. Clin. Invest. 106, 523–531 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Desreumaux, P. et al. Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor γ (PPARγ) heterodimer. A basis for new therapeutic strategies. J. Exp. Med. 193, 827–838 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Su, C. G. et al. A novel therapy for colitis utilizing PPAR-γ ligands to inhibit the epithelial inflammatory response. J. Clin. Invest. 104, 383–389 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Feinstein, D. L. et al. Peroxisome proliferator-activated receptor-γ agonists prevent experimental autoimmune encephalomyelitis. Ann. Neurol. 51, 694–702 (2002).

    CAS  PubMed  Google Scholar 

  125. Diab, A. et al. Peroxisome proliferator-activated receptor-γ agonist 15-deoxy-Δ12,14-prostaglandin J2 ameliorates experimental autoimmune encephalomyelitis. J. Immunol. 168, 2508–2515 (2002).

    CAS  PubMed  Google Scholar 

  126. Ellis, C. N. et al. Troglitazone improves psoriasis and normalizes models of proliferative skin disease: ligands for peroxisome proliferator-activated receptor-γ inhibit keratinocyte proliferation. Arch. Dermatol. 136, 609–616 (2000).

    CAS  PubMed  Google Scholar 

  127. Lewis, J. D. & Lichetenstein, G. R. An open-label trial of the PPAR-γ ligand rosiglitazone for active ulcerative colitis. Am. J. Gastroenterol. 96, 3323–3328 (2001).

    CAS  PubMed  Google Scholar 

  128. Kornbluth, A. What happened to drug trials in ulcerative colitis? Problems, PPARs, placebos, and (possible) progress. Am. J. Gastroenterol. 96, 3232–3234 (2001).

    CAS  PubMed  Google Scholar 

  129. Wagner, B. L. et al. Promoter-specific roles for liver X receptor/corepressor complexes in the regulation of ABCA1 and SREBP1 gene expression. Mol. Cell. Biol. 23, 5780–5789 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Barish, G. D. et al. A nuclear receptor atlas: macrophage activation. Mol. Endocrinol. 19, 2466–2477 (2005). This paper reports the use of quantitative real-time PCR to provide a comprehensive assessment of changes in expression of the 49 members of the mouse nuclear-receptor superfamily in macrophages.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We apologize to our many colleagues whose work could not be cited owing to space limitations. We thank A.Z. Howarth for assistance with preparation of the manuscript and members of the laboratory for stimulating discussions. This work was supported by grants from the National Institutes of Health and the Donald W. Reynolds Cardiovascular Clinical Research Center at Stanford University.

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FURTHER INFORMATION

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Nuclear Receptor Signalling Atlas

Glossary

Metabolic syndrome

A group of metabolic abnormalities that include a combination of insulin resistance, obesity, hypertension, hypertriglyceridaemia and low levels of high-density lipoprotein.

Heat-shock protein

(HSP) Also known as stress proteins. These are a broad group of proteins that are constitutively expressed and/or induced when a cell is exposed to various types of environmental stressors including heat, cold and oxygen deprivation. They often function as chaperones to facilitate appropriate folding and subcellular localization. In the case of steroid-hormone receptors, HSPs have essential roles in protein folding and maintaining the receptors in an inactive state in the absence of hormone.

Hypothalamic–pituitary–adrenal axis

(HPA axis) An important part of the neuroendocrine system that controls reactions to stress and regulates various body processes including digestion, the immune system and energy use. The hypothalamus releases corticotrophin-releasing factor (CRF), which is transported to the anterior lobe of the pituitary, where it stimulates release of stored adrenocorticotropic hormone (ACTH). Circulating ACTH acts on the adrenal gland to stimulate biosynthesis of corticosteroids from cholesterol.

Oxysterol

Oxygenated derivatives of cholesterol that can be generated by several different cellular enzymes. Specific oxysterols, such as 24S-hydroxycholesterol and 22R-hydroxysterol, are generated in the setting of excess levels of free cholesterol. These oxysterols function to inhibit cholesterol synthesis/influx pathways by preventing activation of sterol-regulatory-element-binding proteins (SREBPs) and stimulating cholesterol-removal pathways by stimulating liver X receptors.

Chromatin immunoprecipitation (ChIP) assay

A powerful method used to assess the physical association of a known nuclear protein with a candidate target locus in vivo. Cells are first treated with a 'zero-length crosslinker' (formaldehyde) which crosslinks protein to DNA, either directly or through other proteins. Chromatin is then sheared to less than 500 base pairs, and the protein is immunoprecipitated. If the candidate target gene is co-precipitated (as measured by PCR), the target locus is likely to bind the protein, directly or indirectly, in vivo.

Sumoylation

The post-translational modification of proteins that involves the covalent attachment of small ubiquitin-like modifier (SUMO) and regulates the interactions of those proteins with other macromolecules.

REL-homology domain

A conserved domain of 300 amino acids that is found in the amino-terminal portion of nuclear factor-kB (NF-κB) family members. It contains motifs that are responsible for dimerization, nuclear translocation and binding to NF-κB-binding motifs that are present in DNA.

Glucocorticoids

Cholesterol-derived hormones produced by the adrenal gland that regulate gene expression by diffusing into cells and activating the glucocorticoid receptor. Synthetic derivatives are widely used to suppress a wide range of inflammatory conditions. Commonly used derivatives include dexamethasone and prednisolone.

Foam cells

Lipid-loaded macrophages originating from monocytes or from smooth-muscle cells, accumulating in the subendothelial space during the development of fatty streaks and atherosclerotic lesions.

Type 2 diabetes mellitus

A disorder of glucose homeostasis characterized by inappropriately increased blood glucose levels and resistance of tissues to the action of insulin. Recent studies indicate that inflammation in adipose tissue, liver and muscle contributes to the insulin-resistant state characteristic of type 2 diabetes mellitus, and that anti-diabetic actions of peroxisome-proliferator-activated receptor-γ (PPARγ) agonists result in part from anti-inflammatory effects in these tissues.

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Glass, C., Ogawa, S. Combinatorial roles of nuclear receptors in inflammation and immunity. Nat Rev Immunol 6, 44–55 (2006). https://doi.org/10.1038/nri1748

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