Pharmacologic inhibition of RORγt regulates th17 signature gene expression and suppresses cutaneous inflammation in vivo

Journal of Immunology

Volumn 192, Issue 6, 2014, Pages 2564-2575

  Skepner, Jill ^a   Ramesh, Radha ^a   Trocha, Mark ^a   Schmidt, Darby ^a   Baloglu, Erkan ^a   Lobera, Mercedes ^a   Carlson, Thaddeus ^a   Hill, Jonathan ^a   Orband Miller, Lisa A ^a   Barnes, Ashley ^b   Boudjelal, Mohamed ^b   Sundrud, Mark ^a   Ghosh, Shomir ^a   Yang, Jianfei ^a  

^a GLAXOSMITHKLINE   (United States)

^b GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIINFLAMMATORY AGENT; BENZOFURAN DERIVATIVE; GAMMA INTERFERON; INTERLEUKIN 17; INTERLEUKIN 23; LUCIFERASE; RETINOID RELATED ORPHAN RECEPTOR GAMMA; TMP 536; TMP 774; TMP 776; TMP 778; TMP 780; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ADULT; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CD4 LYMPHOCYTE COUNT; CD8+ T LYMPHOCYTE; CELL DIFFERENTIATION; CONCENTRATION (PARAMETERS); CONTROLLED STUDY; CYTOKINE PRODUCTION; DERMATITIS; DRUG EFFICACY; DRUG POTENCY; DRUG STRUCTURE; FEMALE; GENE EXPRESSION; HUMAN; HUMAN CELL; HUMAN TISSUE; IC 50; IN VIVO STUDY; INVERSE AGONISM; MEMORY T LYMPHOCYTE; MONONUCLEAR CELL; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN TARGETING; PSORIASIS; SKINFOLD THICKNESS; TH17 CELL;

ADULT; ANIMALS; CD4-POSITIVE T-LYMPHOCYTES; CELL DIFFERENTIATION; CELLS, CULTURED; DERMATITIS; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; FLUORESCENCE RESONANCE ENERGY TRANSFER; HEK293 CELLS; HETEROCYCLIC COMPOUNDS WITH 4 OR MORE RINGS; HUMANS; INTERLEUKIN-17; JURKAT CELLS; LEUKOCYTES, MONONUCLEAR; MICE; MICE, INBRED BALB C; MOLECULAR STRUCTURE; NUCLEAR RECEPTOR SUBFAMILY 1, GROUP F, MEMBER 3; OLIGONUCLEOTIDE ARRAY SEQUENCE ANALYSIS; PSORIASIS; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; SKIN; SMALL MOLECULE LIBRARIES; TH17 CELLS; TRANSCRIPTOME;

EID: 84897506518     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.1302190     Document Type: Article

References (43)

1. McGeachy, M. J., and D. J. Cua. 2008. Th17 cell differentiation: the long and winding road. Immunity 28: 445-453.
2. Miossec, P., T. Korn, and V. K. Kuchroo. 2009. Interleukin-17 and type 17 helper T cells. N. Engl. J. Med. 361: 888-898.
3. Hueber, W., D. D. Patel, T. Dryja, A. M. Wright, I. Koroleva, G. Bruin, C. Antoni, Z. Draelos, M. H. Gold, P. Durez, et al; Psoriasis Study Group; Rheumatoid Arthritis Study Group; Uveitis Study Group. 2010. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci. Transl. Med. 2: 52ra72.
4. Dong, C. 2008. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat. Rev. Immunol. 8: 337-348.
5. Leonardi, C., R. Matheson, C. Zachariae, G. Cameron, L. Li, E. Edson-Heredia, D. Braun, and S. Banerjee. 2012. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N. Engl. J. Med. 366: 1190-1199.
6. Papp, K. A., C. Leonardi, A. Menter, J. P. Ortonne, J. G. Krueger, G. Kricorian, G. Aras, J. Li, C. B. Russell, E. H. Thompson, and S. Baumgartner. 2012. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N. Engl. J. Med. 366: 1181-1189.
7. Ivanov, I. I., B. S. McKenzie, L. Zhou, C. E. Tadokoro, A. Lepelley, J. J. Lafaille, D. J. Cua, and D. R. Littman. 2006. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126: 1121-1133.
8. Acosta-Rodriguez, E. V., G. Napolitani, A. Lanzavecchia, and F. Sallusto. 2007. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat. Immunol. 8: 942-949.
9. Res, P. C., G. Piskin, O. J. de Boer, C. M. van der Loos, P. Teeling, J. D. Bos, and M. B. Teunissen. 2010. Overrepresentation of IL-17A and IL-22 producing CD8 T cells in lesional skin suggests their involvement in the pathogenesis of psoriasis. PLoS ONE 5: e14108.
10. Laggner, U., P. Di Meglio, G. K. Perera, C. Hundhausen, K. E. Lacy, N. Ali, C. H. Smith, A. C. Hayday, B. J. Nickoloff, and F. O. Nestle. 2011. Identification of a novel proinflammatory human skin-homing Vg9Vd2 T cell subset with a potential role in psoriasis. J. Immunol. 187: 2783-2793.
11. Hijnen, D., E. F. Knol, Y. Y. Gent, B. Giovannone, J. P. Beijn, T. S. Kupper, C. A. Bruijnzeel-Koomen, and R. A. Clark. 2013. CD8(+) T cells in the lesional skin of atopic dermatitis and psoriasis patients are an important source of IFNgamma, IL-13, IL-17, and IL-22. J. Invest Dermatol. 133: 973-979.
12. Cua, D. J., J. Sherlock, Y. Chen, C. A. Murphy, B. Joyce, B. Seymour, L. Lucian, W. To, S. Kwan, T. Churakova, et al. 2003. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421: 744-748.
13. Petermann, F., V. Rothhammer, M. C. Claussen, J. D. Haas, L. R. Blanco, S. Heink, I. Prinz, B. Hemmer, V. K. Kuchroo, M. Oukka, and T. Korn. 2010. gd T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism. Immunity 33: 351-363.
14. Sutton, C. E., S. J. Lalor, C. M. Sweeney, C. F. Brereton, E. C. Lavelle, and K. H. Mills. 2009. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 31: 331-341.
15. Langrish, C. L., Y. Chen, W. M. Blumenschein, J. Mattson, B. Basham, J. D. Sedgwick, T. McClanahan, R. A. Kastelein, and D. J. Cua. 2005. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201: 233-240.
16. McGeachy, M. J., Y. Chen, C. M. Tato, A. Laurence, B. Joyce-Shaikh, W. M. Blumenschein, T. K. McClanahan, J. J. O'Shea, and D. J. Cua. 2009. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat. Immunol. 10: 314-324.
17. Lee, Y., A. Awasthi, N. Yosef, F. J. Quintana, S. Xiao, A. Peters, C. Wu, M. Kleinewietfeld, S. Kunder, D. A. Hafler, et al. 2012. Induction and molecular signature of pathogenic TH17 cells. Nat. Immunol. 13: 991-999.
18. Cargill, M., S. J. Schrodi, M. Chang, V. E. Garcia, R. Brandon, K. P. Callis, N. Matsunami, K. G. Ardlie, D. Civello, J. J. Catanese, et al. 2007. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80: 273-290.
19. Rahman, P., R. D. Inman, W. P. Maksymowych, J. P. Reeve, L. Peddle, and D. D. Gladman. 2009. Association of interleukin 23 receptor variants with psoriatic arthritis. J. Rheumatol. 36: 137-140.
20. Capon, F., P. Di Meglio, J. Szaub, N. J. Prescott, C. Dunster, L. Baumber, K. Timms, A. Gutin, V. Abkevic, A. D. Burden, et al. 2007. Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum. Genet. 122: 201-206.
21. Leonardi, C. L., A. B. Kimball, K. A. Papp, N. Yeilding, C. Guzzo, Y. Wang, S. Li, L. T. Dooley, and K. B. Gordon; PHOENIX 1 study investigators. 2008. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, doubleblind, placebo-controlled trial (PHOENIX 1). Lancet 371: 1665-1674.
22. Huh, J. R., M. W. Leung, P. Huang, D. A. Ryan, M. R. Krout, R. R. Malapaka, J. Chow, N. Manel, M. Ciofani, S. V. Kim, et al. 2011. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgt activity. Nature 472: 486-490.
23. Solt, L. A., N. Kumar, P. Nuhant, Y. Wang, J. L. Lauer, J. Liu, M. A. Istrate, T. M. Kamenecka, W. R. Roush, D. Vidović, et al. 2011. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472: 491-494.
24. Xu, T., X. Wang, B. Zhong, R. I. Nurieva, S. Ding, and C. Dong. 2011. Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORgamma t protein. J. Biol. Chem. 286: 22707-22710.
25. Yang, J., B. E. Castle, A. Hanidu, L. Stevens, Y. Yu, X. Li, C. Stearns, V. Papov, D. Rajotte, and J. Li. 2005. Sphingosine kinase 1 is a negative regulator of CD4+ Th1 cells. J. Immunol. 175: 6580-6588.
26. Yang, J., M. Yang, T. M. Htut, X. Ouyang, A. Hanidu, X. Li, R. Sellati, H. Jiang, S. Zhang, H. Li, et al. 2008. Epstein-Barr virus-induced gene 3 negatively regulates IL-17, IL-22 and RORgamma t. Eur. J. Immunol. 38: 1204-1214.
27. Yang, J., X. Li, A. Hanidu, T. M. Htut, R. Sellati, L. Wang, H. Jiang, and J. Li. 2010. Proviral integration site 2 is required for interleukin-6 expression induced by interleukin-1, tumour necrosis factor-A and lipopolysaccharide. Immunology 131: 174-182.
28. Xie, H., M. S. Sadim, and Z. Sun. 2005. RORgammat recruits steroid receptor coactivators to ensure thymocyte survival. J. Immunol. 175: 3800-3809.
29. Intlekofer, A. M., A. Banerjee, N. Takemoto, S. M. Gordon, C. S. Dejong, H. Shin, C. A. Hunter, E. J. Wherry, T. Lindsten, and S. L. Reiner. 2008. Anomalous type 17 response to viral infection by CD8+ T cells lacking T-bet and eomesodermin. Science 321: 408-411.
30. Kondo, T., H. Takata, F. Matsuki, and M. Takiguchi. 2009. Cutting edge: phenotypic characterization and differentiation of human CD8+ T cells producing IL-17. J. Immunol. 182: 1794-1798.
31. Singh, S. P., H. H. Zhang, J. F. Foley, M. N. Hedrick, and J. M. Farber. 2008. Human T cells that are able to produce IL-17 express the chemokine receptor CCR6. J. Immunol. 180: 214-221.
32. Annunziato, F., L. Cosmi, V. Santarlasci, L. Maggi, F. Liotta, B. Mazzinghi, E. Parente, L. Filì, S. Ferri, F. Frosali, et al. 2007. Phenotypic and functional features of human Th17 cells. J. Exp. Med. 204: 1849-1861.
33. Becher, B., and S. Pantelyushin. 2012. Hiding under the skin: interleukin-17-producing γδ T cells go under the skin? Nat. Med. 18: 1748-1750.
34. Cai, Y., X. Shen, C. Ding, C. Qi, K. Li, X. Li, V. R. Jala, H. G. Zhang, T. Wang, J. Zheng, and J. Yan. 2011. Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity 35: 596-610.
35. Pantelyushin, S., S. Haak, B. Ingold, P. Kulig, F. L. Heppner, A. A. Navarini, and B. Becher. 2012. Rorγt+ innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in mice. J. Clin. Invest. 122: 2252-2256.
36. Gilliet, M., C. Conrad, M. Geiges, A. Cozzio, W. Thürlimann, G. Burg, F. O. Nestle, and R. Dummer. 2004. Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors. Arch. Dermatol. 140: 1490-1495.
37. van der Fits, L., S. Mourits, J. S. Voerman, M. Kant, L. Boon, J. D. Laman, F. Cornelissen, A. M. Mus, E. Florencia, E. P. Prens, and E. Lubberts. 2009. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J. Immunol. 182: 5836-5845.
38. Rich, P., B. Sigurgeirsson, D. P. Thaci, J. P. Ortonne, C. Paul, R. E. Schopf, A. Morita, K. Roseau, E. Harfst, A. Guettner, et al. 2013. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study. Br. J. Dermatol. 168: 402-411.
39. Papp, K. A., R. G. Langley, B. Sigurgeirsson, M. Abe, D. R. Baker, P. Konno, S. Haemmerle, H. J. Thurston, C. Papavassilis, and H. B. Richards. 2013. Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study. Br. J. Dermatol. 168: 412-421.
40. Zheng, Y., D. M. Danilenko, P. Valdez, I. Kasman, J. Eastham-Anderson, J. Wu, and W. Ouyang. 2007. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445: 648-651.
41. Van Belle, A. B., M. de Heusch, M. M. Lemaire, E. Hendrickx, G. Warnier, K. Dunussi-Joannopoulos, L. A. Fouser, J. C. Renauld, and L. Dumoutier. 2012. IL-22 is required for imiquimod-induced psoriasiform skin inflammation in mice. J. Immunol. 188: 462-469.
42. Yang, J., J. Skepner, T. Mark, and S. Ghosh. 2013. Small molecule inhibitors targeting the Th17 cell transcription factor RORgammat for the treatment of autoimmune diseases. J. Clin. Cell. Immunol. 4: e111-e112.
43. Huh, J. R., and D. R. Littman. 2012. Small molecule inhibitors of RORgt: targeting Th17 cells and other applications. Eur. J. Immunol. 42: 2232-2237.