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  • Review Article
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Targeting signal transduction as a strategy to treat inflammatory diseases

Nature Reviews Drug Discovery volume 5, pages 549–563 (2006)Cite this article

Key Points

  • Recent progress in our understanding of signal transduction pathways that are activated during inflammation has led to new targets for anti-inflammatory drugs being explored and new drugs being developed.

  • Targets have been identified in the nuclear factor-κB (NF-κB), p38 mitogen-activated protein kinase (MAPK) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. Drugs that target inhibitor of NF-κB (IκB) kinase and p38 MAPK are in clinical development for rheumatoid arthritis, and a JAK3 inhibitor is being explored as an immunosuppressant.

  • Initiation of signalling by the pro-inflammatory cytokines tumour-necrosis factor, interleukin-1 (IL-1), Toll-like receptors (TLRs) and Nod-like receptors (NLRs) involves the assembly of multi-protein complexes. Targeting such complexes might yield specific agents that block inflammation.

  • TLRs and NLRs are increasingly being implicated in inflammatory diseases and targeting them selectively might have potent anti-inflammatory effects.

  • Recently, glucocorticoids have been shown to block certain genes via interference with p65–interferon regulatory factor 3 complexes activated by TLR4, with TLR3 signalling not being affected. This might prevent inflammation but leave anti-viral responses intact.

Abstract

Inflammatory diseases are a major burden on humanity, despite recent successes with biopharmaceuticals. Lack of responsiveness and resistance to these drugs, delivery problems and cost of manufacture of biopharmaceuticals mean that the search for new anti-inflammatory agents continues. Progress in our understanding of inflammatory signalling pathways has identified new targets, notably in pathways involving NF-κB, p38 MAP kinase, T lymphocyte activation and JAK/STAT. Other targets such as transcription factor complexes and components of pathways activated by TNF, Toll-like receptors and Nod-like receptors also present possibilities, and might show efficacy without being limited by effects on host defence. The challenge is to place a value on one target relative to another, and to devise strategies to modulate them.

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Figure 1: The four classical signalling pathways.
Figure 2: Nuclear factor-κB signalling pathways.
Figure 3: Janus kinase/signal transducer of activated transcription pathway.
Figure 4: T lymphocyte activation.
Figure 5: Pathways involving Toll-like receptors and Nod-like receptors.
Figure 6: Signal-specific inhibition of inflammatory gene expression by glucocorticoids.

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References

  1. Olsen, N. J. & Stein, C. M. New drugs for rheumatoid arthritis. N. Engl. J. Med. 350, 2167–2179 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Wang, D., Wang, M., Cheng, Y. & Fitzgerald, G. A. Cardiovascular hazard and non-steroidal anti-inflammatory drugs. Curr. Opin. Pharmacol. 5, 204–210 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Fleischmann, R. & Yocum, D. Does safety make a difference in selecting the right TNF antagonist? Arthritis Res. Ther. 6, S12–S18 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Edwards, J. C. et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 350, 2572–2581 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Kremer, J. M. et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N. Engl. J. Med. 349, 1907–1915 (2003). References 4 and 5 describe the clinical efficacy of targeting T cells in rheumatoid arthritis using anti-CD20 and CTLA4Ig.

    Article  CAS  PubMed  Google Scholar 

  6. Sandborn, W. J. et al. Natalizumab induction and maintenance therapy for Crohn's disease. N. Engl. J. Med. 353, 1912–1925 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Spina, D. The potential of PDE4 inhibitors in respiratory disease. Curr. Drug Targets Inflamm. Allergy 3, 231–236 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Chung, K. F. Phosphodiesterase inhibitors in airways disease. Eur. J. Pharmacol. 533, 110–117 (2006).

    Article  CAS  Google Scholar 

  9. Corbin, J. D. & Francis, S. H. Cyclic GMP phosphodiesterase-5: target of sildenafil. J. Biol. Chem. 274, 13729–13732 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Herbst, R. S. & Kies, M. S. Gefitinib: current and future status in cancer therapy. Clin. Adv. Hematol. Oncol. 1, 466–472 (2003).

    PubMed  Google Scholar 

  11. Perez-Soler, R. et al. Final results from a Phase II study of erlotinib monotherapy in patients with advanced non-small cell lung cancer following failure of platinum-based chemotherapy. Lung Cancer 41, S246 (2003).

    Article  Google Scholar 

  12. Piccart-Gebhart, M. J. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353, 1659–1672 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Druker, B. J. et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukaemia and acute lymphoblastic leukaemia with the Philadelphia chromosome. N. Engl. J. Med. 344, 1038–1042 (2001). The first clinical analysis of imatinib (Gleevec) in the treatment of CML. Imatinib was found to be highly efficacious in the treatment of this disorder.

    Article  CAS  PubMed  Google Scholar 

  14. Miossec, P. The role of interleukin 1 in the pathogenesis of rheumatoid arthritis. Clin. Exp. Rheumatol. 5, 305–308 (1987).

    CAS  PubMed  Google Scholar 

  15. Brennan, F. M., Maini, R. N. & Feldmann, M. TNF-α — a pivotal role in rheumatoid arthritis? Br. J. Rheumatol. 31, 293–298 (1992).

    Article  CAS  PubMed  Google Scholar 

  16. Gay, N. J. & Keith, F. J. Drosophila Toll and IL-1 receptor. Nature 351, 355–356 (1991).

    Article  CAS  PubMed  Google Scholar 

  17. O'Neill, L. A. & Greene, C. Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants. J. Leukoc. Biol. 63, 650–657 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. O'Neill, L. A. Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases. Curr. Opin. Pharmacol. 3, 3396–3403 (2003).

    Article  CAS  Google Scholar 

  19. Sen, R. & Baltimore, D. Inducibility of κ-immunoglobulin enhancer-binding protein NF-κB by a posttranslational mechanism. Cell 47, 921–928 (1986).

    Article  CAS  PubMed  Google Scholar 

  20. Osborn, L., Kunkel, S. & Nabel, G. J. Tumor necrosis factor-α and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor κB. Proc. Natl Acad. Sci. USA 86, 2336–2340 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. O'Neill, L. A. How Toll-like receptors signal: what we know and what we don't know. Curr. Opin. Immunol. 18, 3–9 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Martinon, F. & Tschopp, J. NLRs join TLRs as innate sensors of pathogens. Trends Immunol. 26, 447–454 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Kolls, J. K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467–476 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Siebenlist, U., Brown, K. & Claudio, E. Control of lymphocyte development by nuclear factor-κB. Nature Rev. Immunol. 5, 435–445 (2005).

    Article  CAS  Google Scholar 

  25. Moynagh, P. N. The NF-κB pathway. J. Cell Sci. 118, 4589–4592 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Bonnizzi, G. et al. Activation of IKKα target genes depends on recognition of specific κB binding sites by RelB:p52 dimers. EMBO J. 23, 4202–4210 (2004).

    Article  CAS  Google Scholar 

  27. Karin, M., Yamamoto, Y. & May Wang, Q. The IKK NF-κB system: a treasure trove for drug development. Nature Rev. Drug Discov. 3, 17–26 (2004).

    Article  CAS  Google Scholar 

  28. di Meglio, P., Ianaro, A. & Ghosh, S. Amelioration of acute inflammation by systemic administration of a cell-permeable peptide inhibitor of NF-κB activation. Arthritis Rheum. 52, 951–958 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Luo, J. L., Kamata, H. & Karin, M. IKK/NF-κB signaling: balancing life and death — a new approach to cancer therapy. J. Clin. Invest. 115, 2625–2632 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Spano, J. P., Bay, J. O., Blay, J. Y. & Rixe, O. Proteasome inhibition: a new approach for the treatment of malignancies. Bull. Cancer 92, E61–E6, 945–952 (2005).

    PubMed  Google Scholar 

  31. Proteolix, Inc. Proteolix Programs [online], (2006).

  32. Han, J., Lee, J. D., Bibbs, L. & Ulevitch, R. J. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265, 808–811 (1994).

    Article  CAS  PubMed  Google Scholar 

  33. Freshney, N. W. et al. Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell 78, 1039–1049 (1994).

    Article  CAS  PubMed  Google Scholar 

  34. Lee, J. C. et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739–746 (1994). Reports the identification of p38 and its targeting by pyridinyl imidazole compounds.

    Article  CAS  PubMed  Google Scholar 

  35. Kracht, M. & Saklatvala, J. Transcriptional and post-transcriptional control of gene expression in inflammation. Cytokine 20, 91–106 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Shim, J. H. et al. TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev. 19, 2668–2681 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dean, J. L., Sully, G., Clark, A. R. & Saklatvala, J. The involvement of AU-rich element-binding proteins in p38 mitogen-activated protein kinase pathway-mediated mRNA stabilisation. Cell Signal. 16, 1113–1121 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Dominguez, C., Powers, D. A. & Tamayo, N. p38 MAP kinase inhibitors: many are made, but few are chosen. Curr. Opin. Drug Discov. Devel. 8, 421–430 (2005).

    CAS  PubMed  Google Scholar 

  39. Goldstein, D. M. & Gabriel, T. Pathway to the clinic: inhibition of p38 MAP kinase. A review of ten chemotypes selected for development. Curr. Top. Med. Chem. 5, 1017–1029 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Vertex, Inc. Vertex reports investigational p38 MAP kinase inhibitor, VX-702, meets primary objectives in Phase II clinical study in rheumatoid arthritis [online], (2006).

  41. Waetzig, V. & Herdegen, T. Context-specific inhibition of JNKs: overcoming the dilemma of protection and damage. Trends Pharmacol. Sci. 26, 455–461 (2005).

    CAS  PubMed  Google Scholar 

  42. Manning, A. M. & Davis, R. J. Targeting JNK for therapeutic benefit: from junk to gold. Nature Rev. Drug Discov. 2, 554–565 (2003).

    Article  CAS  Google Scholar 

  43. Eynott, P. R., Adcock, I. M. & Chung, P. The effects of a selective c-Jun N-terminal kinase inhibition in a sensitized Brown Norway rat model of allergic asthma. Am. J. Respir. Crit. Care Med. 49, S102 (2001).

    Google Scholar 

  44. Han, Z. et al. Jun-N-terminal kinase in rheumatoid arthritis. J. Pharm. Exp. Ther. 291, 124–130 (1999).

    CAS  Google Scholar 

  45. Kassel, O. et al. Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1. EMBO J. 20, 7108–7116 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lasa, M., Abraham, S. M., Boucheron, C., Saklatvala, J. & Clark, A. R. Dexamethasone causes sustained expression of MKP-1 and phosphatase-mediated inhibition of MAPK p38. Mol. Cell. Biol. 22, 7802–7811 (2002). References 45 and 46 describe induction of MAPK phosphatase 1 by glucocorticoids, which inactivates p38 MAPK. This is likely to be an important mechanism of action through which steroids evoke anti-inflammatory responses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. O'Shea, J. J., Pesu, M., Borie, D. C. & Changelian, P. S. A new modality for immunosuppression: targeting the JAK/STAT pathway. Nature Rev. Drug Discov. 3, 555–564 (2004).

    Article  CAS  Google Scholar 

  48. Changelian, P. S. et al. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science 302, 875–878 (2003). The first report of a JAK3-specific inhibitor that has significant immunosuppressive effects.

    Article  CAS  PubMed  Google Scholar 

  49. Baslund, B. et al. Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study. Arthritis Rheum. 52, 2686–2692 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Bissonnette, R. et al. A randomized, multicenter, double-blind, placebo-controlled phase 2 trial of ISA247 in patients with chronic plaque psoriasis. J. Am. Acad. Dermatol. 54, 472–478 (2006).

    Article  PubMed  Google Scholar 

  51. Chiba, K., Matsuyuki, H., Maeda, Y. & Sugahara, K. Role of sphingosine 1-phosphate receptor type I in lymphocyte egress from secondary lymphoid tissues and thymus. Cell. Mol. Immunol. 3, 11–19 (2006).

    CAS  PubMed  Google Scholar 

  52. Fujino, M. et al. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J. Pharmacol. Exp. Ther. 305, 70–77 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Medical News Today. Multiple sclerosis — FTY720, a novel once-daily oral medication, shows promising results [online], (2005).

  54. Young, D. A. & Nickerson-Nutter, C. L. mTOR — beyond transplantation. Curr. Opin. Pharmacol. 5, 418–423 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Ghosh, P., Buchholz, M. A., Yano, S., Taub, D. & Longo, D. L. Effect of rapamycin on the cyclosporine-resistant CD28-mediated costimulatory pathway. Blood 99, 4517–4524 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Mayer, D. F. & Kushwaha, S. S. Transplant immunosuppressant agents and their role in autoimmune rheumatic diseases. Curr. Opin. Rheumatol. 15, 219–225 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Lehle, K., Birnbaum, D. E. & Preuner, J. G. Predominant inhibition of interleukin-6 synthesis in patient-specific endothelial cells by mTOR inhibitors below a concentration range where cell proliferation is affected and mitotic arrest takes place. Transplant Proc. 37, 159–161 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Dancey, J. E. Inhibitors of the mammalian target of rapamycin. Expert Opin. Investig. Drugs 14, 313–328 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Moseley, T. A., Haudenschild, D. R., Rose, L. & Reddi, A. H. Interleukin-17 and IL-17 receptors. Cytokine Growth Factor Rev. 14, 155–174 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Lubberts, E. The role of IL-17 and family members in the pathogenesis of arthritis. Curr. Opin. Investig. Drugs 4, 572–577 (2003).

    CAS  PubMed  Google Scholar 

  61. Hee, M. M. et al. Small-molecule inhibition of TNF-α. Science 11, 1022–1025 (2005). Describes a small-molecule inhibitor of TNF that disrupts the TNFα trimer, thereby abolishing its biological activity.

    Article  CAS  Google Scholar 

  62. Bouwmeester, T. et al. A physical and functional map of the human TNF/NF-κB signal transduction pathway. Nature Cell Biol. 6, 97–105 (2004). Presents a proteomic analysis of TNF signal transduction, documenting 221 molecular associations.

    Article  CAS  PubMed  Google Scholar 

  63. Janssens, S. & Beyaert, R. Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members. Mol. Cell 11, 293–302 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. O'Neill, L. A., Fitzgerald, K. A. & Bowie, A. G. The Toll–IL-1 receptor adaptor family grows to five members. Trends Immunol. 24, 286–290 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Fitzgerald, K. A. et al. IKKε and TBK1 are essential components of the IRF3 signaling pathway. Nature Immunol. 4, 491–496 (2003).

    Article  CAS  Google Scholar 

  66. Sharma, S. et al. Triggering the interferon antiviral response through an IKK-related pathway. Science 300, 1148–1151 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Hacker, H. et al. Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439, 204–207 (2006).

    Article  PubMed  CAS  Google Scholar 

  68. Oganesyan, G. Critical role of TRAF3 in the Toll-like receptor-dependent and-independent antiviral response. Nature 439, 208–211 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Honda, K. et al. Spatiotemporal regulation of MyD88–IRF-7 signalling for robust type-I interferon induction. Nature 434, 1035–1040 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Uematsu, S. et al. IRAK-1 plays an essential role for TLR7- and TLR9-mediated interferon-α induction. J. Exp. Med. 201, 915–923 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Siebl, R. et al. Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium. Am. J. Pathol. 162, 1221–1227 (2003). Describes the first indication of a role for TLR2 in rheumatoid arthritis.

    Article  Google Scholar 

  72. Leadbetter, E. A. et al. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Lau, C. M. et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202, 1171–1177 (2005). References 72 and 73 implicate TLR9 and TLR7 respectively in autoantibody production.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bartfai, T. et al. A low molecular weight mimic of Toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses. Proc. Natl Acad. Sci. USA 100, 7971–7976 (2003). Describes a peptide that can interfere with the recruitment of MyD88 to the type I IL-1R and so prevent signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Harte, M. et al. The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defence. J. Exp. Med. 197, 343–351 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. McCoy, S. L., Kurtz, S. E., MacArthur, C. J., Trune, D. R. & Hefeneider, S. H. Identification of a peptide derived from Vaccinia virus A52R protein that inhibits cytokine secretion in response to TLR-dependent signalling and reduces in vivo bacterial-induced inflammation. J. Immunol. 174, 3006–3014 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Holtmann, M. M. RDP-58 (Sangstat medical). IDrugs 6, 1188–1194 (2003).

    CAS  PubMed  Google Scholar 

  78. Travis, S. et al. RDP58 is a novel and potentially effective oral therapy for ulcerative colitis. Inflamm. Bowel Dis. 11, 713–719 (2005).

    Article  PubMed  Google Scholar 

  79. Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Strober, W., Murray, P. J., Kitani, A. & Watanabe, T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nature Rev. Immunol. 6, 9–20 (2006).

    Article  CAS  Google Scholar 

  82. Watanabe, T., Kitani, A., Murray, P. J. & Strober, W. NOD2 is a negative regulator of TLR-2-mediated T helper Type I responses. Nature Immunol. 5, 800–808 (2004).

    Article  CAS  Google Scholar 

  83. Maeda, S. et al. Nod2 mutation in Crohn's disease potentiates NF-κB activity and IL-1β processing. Science 307, 734–738 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Kanniganti, T. D. et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440, 233–236 (2006).

    Article  CAS  Google Scholar 

  86. Siegmund, B. & Zeitz, M. Pralnacasan (Vertex pharmaceuticals). IDrugs 6, 154–158 (2003).

    CAS  PubMed  Google Scholar 

  87. Agostini, L. et al. NALP3 forms an IL-1β-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20, 319–325 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Dinarello, C. A. Unravelling the NALP3/IL-1β inflammasome: a big lesson from a small mutation. Immunity 20, 243–246 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Ogawa, S. et al. Molecular determinants of crosstalk between nuclear receptors and Toll-like receptors. Cell 122, 707–721 (2005). Provides a genome-wide analysis of genes whose expression is induced by TLR3 and/or TLR4 and which are inhibited by glucocorticoids. The paper also reports that for genes induced by both TLR3 and TLR4, glucocorticoids inhibit TLR4-induced, but not TLR3-induced, gene expression. This is therefore the first demonstration suggesting that inflammation could be inhibited without limiting TLR-mediated antiviral immunity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wietek, C., Miggin, S. M., Jefferies, C. A. & O'Neill, L. A. Interferon regulatory factor-3-mediated activation of the interferon-sensitive response element by Toll-like receptor (TLR) 4 but not TLR3 requires the p65 subunit of NF-κ. J. Biol. Chem. 278, 50923–50931 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Humbert, M. Ciclesonide: a novel inhaled corticosteroid. Expert Opin. Investig. Drugs 13, 1349–1360 (2005).

    Article  Google Scholar 

  93. Belvisi, M. G. et al. Preclinical profile of ciclesonide, a novel corticosteroid for the treatment of asthma. J. Pharmacol. Exp. Ther. 314, 568–574 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Lee, K. S. PPAR-γ modulates allergic inflammation through up-regulation of PTEN. FASEB J. 19, 1033–1035 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Belvisi, M. G., Hele, D. J. & Birrell, M. A. New advances and potential therapies for the treatment of asthma. BioDrugs 18, 211–223 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. School of Biochemistry and Immunology, Trinity College, Dublin, 2, Ireland

    Luke A. J. O'Neill

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The author is a co-founder of Opsona Therapeutics, which uses immune system research to develop new drugs and vaccines.

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DATABASES

OMIM

Alzheimer's disease

Asthma

Chronic myelogenous leukaemia

Chronic obstructive pulmonary disease

Crohn's disease

Familial cold autoinflammatory syndrome

Inflammatory bowel disease

Muckle–Wells syndrome

Multiple sclerosis

Parkinson's disease

Rheumatoid arthritis

Stroke

Glossary

Biopharmaceuticals

Biological agents, such as antibodies or soluble receptors, that target proteins and have a therapeutic effect.

Host defence

A general term for the body's system to fight infectious agents.

Prostaglandins

Pro-inflammatory lipids that are formed from arachidonic acid by the action of cyclooxygenase enzymes and other downstream synthetases.

Transcription factors

Intracellular proteins that bind to discrete regions of nuclear DNA and regulate gene transcription (mRNA synthesis).

SH2 domain

(Src-homology-2 domain). A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.

Cytokines

Proteins that are released by one cell and affect the physiology of other cells in the vicinity in a particular fashion through binding to specific receptors.

Chemokines

A family of structurally related, small glycoproteins (70–90 amino acids) that have potent leukocyte activation and/or chemotactic activity. They have pivotal roles in innate and acquired immunity.

Signalsome

A multi-protein complex containing the scaffold protein NEMO and the IKKs that regulates NF-κB.

Adaptor proteins

Proteins that usually have several protein–protein interaction domains and increase cellular responses by recruiting other proteins to a complex.

Combinatorial chemistry

The generation of large collections, or 'libraries', of compounds by synthesizing all possible combinations of a set of smaller chemical structures.

Proteasome

A large protein complex that is responsible for degrading intracellular proteins that have been targeted for destruction, usually by the addition of ubiquitin polymers.

ACR20

A measure developed by the American College of Rheumatology to denote a 20% improvement in outcome measures

Phosphatidylinositol turnover

(PI turnover). The breakdown of phosphatidylinositol-4,5-bisphosphate to inositol-1,4,5-trisphosphate and diacylglycerol, which is mediated by phospholipase C.

CpG motifs

DNA oligodeoxynucleotide sequences that include a cytosine–guanosine sequence and certain flanking nucleotides. These motifs, which are common to bacterial and viral DNA and are also incorporated in mammalian DNA, have been found to induce innate immune responses through interaction with Toll-like receptor 9.

Caspase 1

A cysteine protease found in monocytes, lymphocytes, neutrophils, resting and activated T lymphocytes, placenta tissue and several B-lymphoblastoid cell lines.

Inflammasome

A multi-protein complex containing Nod-like receptors, the adaptor protein ASC and caspase 1.

Peptidomimetics

Small-molecule chemicals that mimic the effects of short peptides.

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O'Neill, L. Targeting signal transduction as a strategy to treat inflammatory diseases. Nat Rev Drug Discov 5, 549–563 (2006). https://doi.org/10.1038/nrd2070

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