Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

IL-12, IL-23 and IL-17 in IBD: immunobiology and therapeutic targeting

Abstract

IL-12 and IL-23 are closely related cytokines with important roles in the regulation of tissue inflammation. Converging evidence from studies in mice, human observational studies and population genetics supports the importance of these cytokines in the regulation of mucosal inflammation in the gut in particular. Ustekinumab, a therapeutic antibody targeting both cytokines is now widely licensed for the treatment of Crohn’s disease, including in Europe, the USA, Canada and Japan, whilst agents targeting IL-23 specifically are in late-phase clinical trials. We review the emerging understanding of the biology of IL-12 and IL-23, as well as that of their major downstream cytokines, including IL-17. In particular, we discuss how their biology has influenced the development of clinical trials and therapeutic strategies in IBD, as well as how findings from clinical trials, at times surprising, have in turn refocused our understanding of the underlying biology.

Key points

  • Despite a number of effective therapies in IBD, important treatment targets are still missed in a substantial proportion of patients.

  • Basic science, genetic studies and clinical research have highlighted the importance of the IL-12–T helper 1 (TH1) and IL-23–TH17 pathways in Crohn’s disease and ulcerative colitis.

  • Ustekinumab, an antibody blocking IL-12 and IL-23 has been approved for Crohn’s disease, and the results from a large phase III trial in ulcerative colitis are expected soon.

  • Various drugs designed to interfere with the IL-12–TH1 and IL-23–TH17 pathways, such as IL-23-specific antibodies, oral peptide inhibitors of the IL-23R, JAK inhibitors and retinoid-related orphan receptor-γt (RORγt) antagonists, are in clinical development.

  • Ideally, new therapeutic approaches should fit into existing treatment algorithms; in addition, with an increasing number of treatment modalities, the need is growing for predictive biomarkers to guide treatment decisions.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Structure and signalling of IL-12 and IL-23 via their receptors.
Fig. 2: Biology of IL-12 and IL-23.
Fig. 3: Overview of therapies targeting elements of the IL-12–IL-23 pathway.

Similar content being viewed by others

References

  1. Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Kobayashi, M. et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J. Exp. Med. 170, 827–845 (1989).

    CAS  Google Scholar 

  3. Macatonia, S. E. et al. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J. Immunol. 154, 5071–5079 (1995).

    CAS  PubMed  Google Scholar 

  4. Szabo, S. J. et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100, 655–669 (2000).

    CAS  PubMed  Google Scholar 

  5. Segal, B. M., Dwyer, B. K. & Shevach, E. M. An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J. Exp. Med. 187, 537–546 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. McIntyre, K. W. et al. Reduced incidence and severity of collagen-induced arthritis in interleukin-12-deficient mice. Eur. J. Immunol. 26, 2933–2938 (1996).

    CAS  PubMed  Google Scholar 

  7. Neurath, M. F., Fuss, I., Kelsall, B. L., Stuber, E. & Strober, W. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J. Exp. Med. 182, 1281–1290 (1995).

    CAS  PubMed  Google Scholar 

  8. Fuss, I. J. et al. Anti-interleukin 12 treatment regulates apoptosis of Th1 T cells in experimental colitis in mice. Gastroenterology 117, 1078–1088 (1999).

    CAS  PubMed  Google Scholar 

  9. Cua, D. J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).

    CAS  PubMed  Google Scholar 

  10. Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715–725 (2000).

  11. Yen, D. et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116, 1310–1316 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Patel, D. D. & Kuchroo, V. K. Th17 cell pathway in human immunity: lessons from genetics and therapeutic interventions. Immunity 43, 1040–1051 (2015).

    CAS  PubMed  Google Scholar 

  13. Mannon, P. J. et al. Anti-interleukin-12 antibody for active Crohn’s disease. N. Engl. J. Med. 351, 2069–2079 (2004).

    CAS  PubMed  Google Scholar 

  14. Vignali, D. A. & Kuchroo, V. K. IL-12 family cytokines: immunological playmakers. Nat. Immunol. 13, 722–728 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Collison, L. W. et al. The composition and signaling of the IL-35 receptor are unconventional. Nat. Immunol. 13, 290–299 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Hunter, C. A. & Kastelein, R. Interleukin-27: balancing protective and pathological immunity. Immunity 37, 960–969 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Bloch, Y. et al. Structural activation of pro-inflammatory human cytokine IL-23 by cognate IL-23 receptor enables recruitment of the shared receptor IL-12Rβ1. Immunity 48, 45–58 (2018).

    CAS  PubMed  Google Scholar 

  18. Thierfelder, W. E. et al. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382, 171–174 (1996).

    CAS  PubMed  Google Scholar 

  19. Parham, C. et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 168, 5699–5708 (2002).

    CAS  PubMed  Google Scholar 

  20. Mortha, A. et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343, 1249288 (2014).

    PubMed  PubMed Central  Google Scholar 

  21. Maloy, K. J. & Kullberg, M. C. IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal Immunol. 1, 339–349 (2008).

    CAS  PubMed  Google Scholar 

  22. Hilliard, B. A. et al. Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation. J. Clin. Invest. 110, 843–850 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Jin, J. et al. Epigenetic regulation of the expression of Il12 and Il23 and autoimmune inflammation by the deubiquitinase Trabid. Nat. Immunol. 17, 259–268 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. McKenzie, B. S., Kastelein, R. A. & Cua, D. J. Understanding the IL-23-IL-17 immune pathway. Trends Immunol. 27, 17–23 (2006).

    CAS  PubMed  Google Scholar 

  25. Schnurr, M. et al. Extracellular nucleotide signaling by P2 receptors inhibits IL-12 and enhances IL-23 expression in human dendritic cells: a novel role for the cAMP pathway. Blood 105, 1582–1589 (2005).

    CAS  PubMed  Google Scholar 

  26. Sheibanie, A. F., Tadmori, I., Jing, H., Vassiliou, E. & Ganea, D. Prostaglandin E2 induces IL-23 production in bone marrow-derived dendritic cells. FASEB J. 18, 1318–1320 (2004).

    CAS  PubMed  Google Scholar 

  27. Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 3, 133–146 (2003).

    CAS  PubMed  Google Scholar 

  28. Becker, C. et al. Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells. J. Clin. Invest. 112, 693–706 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Atarashi, K. et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163, 367–380 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  34. Teng, M. W. et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat. Med. 21, 719–729 (2015).

    CAS  PubMed  Google Scholar 

  35. Hirota, K. et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat. Immunol. 12, 255–263 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Gaffen, S. L., Jain, R., Garg, A. V. & Cua, D. J. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat. Rev. Immunol. 14, 585–600 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Adamopoulos, I. E. et al. IL-23 is critical for induction of arthritis, osteoclast formation, and maintenance of bone mass. J. Immunol. 187, 951–959 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Mortha, A. & Burrows, K. Cytokine networks between innate lymphoid cells and myeloid cells. Frontiers Immunol. 9, 191 (2018).

    Google Scholar 

  39. Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Geremia, A. et al. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J. Exp. Med. 208, 1127–1133 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Klose, C. S. N. et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell 157, 340–356 (2014).

    CAS  PubMed  Google Scholar 

  42. Robinette, M. L. et al. Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nat. Immunol. 16, 306–317 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Fuchs, A. et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells. Immunity 38, 769–781 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Klose, C. S. & Artis, D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat. Immunol. 17, 765–774 (2016).

    CAS  PubMed  Google Scholar 

  45. Bernink, J. H. et al. Interleukin-12 and -23 control plasticity of CD127+ group 1 and group 3 innate lymphoid cells in the intestinal lamina propria. Immunity 43, 146–160 (2015).

    CAS  PubMed  Google Scholar 

  46. Duerr, C. U. & Fritz, J. H. Regulation of group 2 innate lymphoid cells. Cytokine 87, 1–8 (2016).

    CAS  Google Scholar 

  47. de Souza, H. S. P., Fiocchi, C. & Iliopoulos, D. The IBD interactome: an integrated view of aetiology, pathogenesis and therapy. Nat. Rev. Gastroenterol. Hepatol. 14, 739–749 (2017).

    PubMed  Google Scholar 

  48. Halme, L. et al. Family and twin studies in inflammatory bowel disease. World J. Gastroenterol. 12, 3668–3672 (2006).

    PubMed  PubMed Central  Google Scholar 

  49. Luo, Y. et al. Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7. Nat. Genet. 49, 186–192 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Cleynen, I. & Vermeire, S. The genetic architecture of inflammatory bowel disease: past, present and future. Curr. Opin. Gastroenterol. 31, 456–463 (2015).

    CAS  PubMed  Google Scholar 

  52. McGovern, D. P., Kugathasan, S. & Cho, J. H. Genetics of inflammatory bowel diseases. Gastroenterology 149, 1163–1176 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Barrett, J. C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat. Genet. 40, 955–962 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat. Genet. 42, 1118–1125 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Sivanesan, D. et al. IL23R (interleukin 23 receptor) variants protective against inflammatory bowel diseases (ibd) display loss of function due to impaired protein stability and intracellular trafficking. J. Biol. Chem. 291, 8673–8685 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Sarin, R., Wu, X. & Abraham, C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T cell functional responses. Proc. Natl Acad. Sci. USA 108, 9560–9565 (2011).

    CAS  PubMed  Google Scholar 

  57. Di Meglio, P. et al. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLOS ONE 6, e17160 (2011).

    PubMed  PubMed Central  Google Scholar 

  58. Pidasheva, S. et al. Functional studies on the IBD susceptibility gene IL23R implicate reduced receptor function in the protective genetic variant R381Q. PLOS ONE 6, e25038 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Oosting, M. et al. Role of interleukin-23 (IL-23) receptor signaling for IL-17 responses in human Lyme disease. Infect. Immun. 79, 4681–4687 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Zwiers, A. et al. Cutting edge: a variant of the IL-23R gene associated with inflammatory bowel disease induces loss of microRNA regulation and enhanced protein production. J. Immunol. 188, 1573–1577 (2012).

    CAS  PubMed  Google Scholar 

  61. Watanabe, T., Kitani, A., Murray, P. J. & Strober, W. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat. Immunol. 5, 800–808 (2004).

    CAS  PubMed  Google Scholar 

  62. Strober, W. & Fuss, I. J. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology 140, 1756–1767 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Fuss, I. J. et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn’s disease LP cells manifest increased secretion of IFN-γ, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J. Immunol. 157, 1261–1270 (1996).

    CAS  PubMed  Google Scholar 

  64. Fuss, I. J. et al. Both IL-12p70 and IL-23 are synthesized during active Crohn’s disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody. Inflamm. Bowel Dis. 12, 9–15 (2006).

    PubMed  Google Scholar 

  65. Liu, Z. et al. Role of interleukin-12 in the induction of mucosal inflammation and abrogation of regulatory T cell function in chronic experimental colitis. Eur. J. Immunol. 31, 1550–1560 (2001).

    CAS  PubMed  Google Scholar 

  66. Rutgeerts, P. et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 353, 2462–2476 (2005).

    CAS  PubMed  Google Scholar 

  67. Reinisch, W. et al. Anrukinzumab, an anti-interleukin 13 monoclonal antibody, in active UC: efficacy and safety from a phase IIa randomised multicentre study. Gut 64, 894–900 (2015).

    CAS  PubMed  Google Scholar 

  68. Cleynen, I. et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet 387, 156–167 (2016).

    PubMed  PubMed Central  Google Scholar 

  69. Langley, R. G. et al. Safety results from a pooled analysis of randomized, controlled phase II and III clinical trials and interim data from an open-label extension trial of the interleukin-12/23 monoclonal antibody, briakinumab, in moderate to severe psoriasis. J. Eur. Acad. Dermatol. Venereol. 27, 1252–1261 (2013).

    CAS  PubMed  Google Scholar 

  70. Ryan, C. et al. Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: a meta-analysis of randomized controlled trials. JAMA 306, 864–871 (2011).

    CAS  PubMed  Google Scholar 

  71. Tzellos, T., Kyrgidis, A., Trigoni, A. & Zouboulis, C. C. Association of ustekinumab and briakinumab with major adverse cardiovascular events: an appraisal of meta-analyses and industry sponsored pooled analyses to date. Dermatoendocrinol. 4, 320–323 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Sandborn, W. J. et al. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology 135, 1130–1141 (2008).

    CAS  PubMed  Google Scholar 

  73. Sandborn, W. J. et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N. Engl. J. Med. 367, 1519–1528 (2012).

    CAS  PubMed  Google Scholar 

  74. Feagan, B. G. et al. Ustekinumab as induction and maintenance therapy for crohn’s disease. N. Engl. J. Med. 375, 1946–1960 (2016).

    CAS  PubMed  Google Scholar 

  75. Rutgeerts, P. et al. Efficacy of ustekinumab for induction and maintenance of endoscopic healing in patients with Crohn’s disease [abstract OP104]. United European Gastroenterol. J. 4 (Suppl. 5.), A1–A156 (2016).

    Google Scholar 

  76. Papp, K. et al. Safety surveillance for ustekinumab and other psoriasis treatments from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). J. Drugs Dermatol. 14, 706–714 (2015).

    CAS  PubMed  Google Scholar 

  77. Ma, C. et al. Clinical, endoscopic and radiographic outcomes with ustekinumab in medically-refractory Crohn’s disease: real world experience from a multicentre cohort. Aliment. Pharmacol. Ther. 45, 1232–1243 (2017).

    CAS  PubMed  Google Scholar 

  78. Khorrami, S. et al. Ustekinumab for the treatment of refractory crohn’s disease: the Spanish experience in a large multicentre open-label cohort. Inflamm. Bowel Dis. 22, 1662–1669 (2016).

    PubMed  Google Scholar 

  79. Wils, P. et al. Subcutaneous ustekinumab provides clinical benefit for two-thirds of patients with Crohn’s disease refractory to anti-tumor necrosis factor agents. Clin. Gastroenterol. Hepatol. 14, 242–250 (2016).

    CAS  PubMed  Google Scholar 

  80. Klinke, D. J. 2nd, Cheng, N. & Chambers, E. Quantifying crosstalk among interferon-γ, interleukin-12, and tumor necrosis factor signaling pathways within a TH1 cell model. Sci. Signal 5, ra32 (2012).

    PubMed  PubMed Central  Google Scholar 

  81. Nagayama, H. et al. IL-12 responsiveness and expression of IL-12 receptor in human peripheral blood monocyte-derived dendritic cells. J. Immunol. 165, 59–66 (2000).

    CAS  PubMed  Google Scholar 

  82. Leal, R. F. et al. Identification of inflammatory mediators in patients with Crohn’s disease unresponsive to anti-TNFα therapy. Gut 64, 233–242 (2015).

    CAS  PubMed  Google Scholar 

  83. Schmitt, H. et al. Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn’s disease. Gut https://doi.org/10.1136/gutjnl-2017-315671 (2018).

  84. Kugathasan, S. et al. Mucosal T cell immunoregulation varies in early and late inflammatory bowel disease. Gut 56, 1696–1705 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Zorzi, F. et al. Distinct profiles of effector cytokines mark the different phases of Crohn’s disease. PLOS ONE 8, e54562 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Kauffman, C. L. et al. A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis. J. Invest. Dermatol. 123, 1037–1044 (2004).

    CAS  PubMed  Google Scholar 

  87. Toichi, E. et al. An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis. J. Immunol. 177, 4917–4926 (2006).

    CAS  PubMed  Google Scholar 

  88. Verstockt, B. et al. Serum markers predict outcome to ustekinumab in patients with refractory Crohn’s disease and provide insides in the mechanism of action. J. Crohn’ Colitis 12, S110 (2018).

    Google Scholar 

  89. Sender, L. Y. et al. CD40 ligand-triggered human dendritic cells mount interleukin-23 responses that are further enhanced by danger signals. Mol. Immunol. 47, 1255–1261 (2010).

    CAS  PubMed  Google Scholar 

  90. Tillack, C. et al. Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-gamma-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment. Gut 63, 567–577 (2014).

    CAS  PubMed  Google Scholar 

  91. Nast, A. et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris — update 2015 — short version — EDF in cooperation with EADV and IPC. J. Eur. Acad. Dermatol. Venereol. 29, 2277–2294 (2015).

    CAS  PubMed  Google Scholar 

  92. Palucka, A. K., Blanck, J. P., Bennett, L., Pascual, V. & Banchereau, J. Cross-regulation of TNF and IFN-α in autoimmune diseases. Proc. Natl Acad. Sci. USA 102, 3372–3377 (2005).

    CAS  PubMed  Google Scholar 

  93. Nestle, F. O. et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-α production. J. Exp. Med. 202, 135–143 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Becker, C. et al. Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis. J. Immunol. 177, 2760–2764 (2006).

    CAS  PubMed  Google Scholar 

  95. Uhlig, H. H. et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25, 309–318 (2006).

    CAS  PubMed  Google Scholar 

  96. Neurath, M. F. IL-12 family members in experimental colitis. Mucosal Immunol. 1 (Suppl. 1), S28–S30 (2008).

    CAS  PubMed  Google Scholar 

  97. Sands, B. E. et al. Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn’s Disease: a phase 2a study. Gastroenterology 153, 77–86 (2017).

    CAS  PubMed  Google Scholar 

  98. Feagan, B. G. et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet 389, 1699–1709 (2017).

    CAS  PubMed  Google Scholar 

  99. Cheng, X., Taranath, R., Mattheakis, L., Bhandari, A. & Liu, D. The biomarker profile of PTG-200, an oral peptide antagonist of IL-23 receptor, tracks with efficacy in a preclinical model of IBD. Gastroenterology 152, S31 (2017).

    Google Scholar 

  100. Soendergaard, C., Bergenheim, F. H., Bjerrum, J. T. & Nielsen, O. H. Targeting JAK-STAT signal transduction in IBD. Pharmacol. Ther. https://doi.org/10.1016/j.pharmthera.2018.07.003 (2018).

    Article  PubMed  Google Scholar 

  101. Schmechel, S. et al. Linking genetic susceptibility to Crohn’s disease with Th17 cell function: IL-22 serum levels are increased in Crohn’s disease and correlate with disease activity and IL23R genotype status. Inflamm. Bowel Dis. 14, 204–212 (2008).

    PubMed  Google Scholar 

  102. Krausgruber, T. et al. T-Bet is a key modulator of IL-23-driven pathogenic CD4+ T cell responses in the intestine. Nat. Commun. 7, 11627 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Aden, K. et al. Epithelial IL-23R signaling licenses protective IL-22 responses in intestinal inflammation. Cell Rep. 16, 2208–2218 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Papp, K. A. et al. Risankizumab versus Ustekinumab for moderate-to-severe plaque psoriasis. N. Engl. J. Med. 376, 1551–1560 (2017).

    CAS  PubMed  Google Scholar 

  105. Langley, R. G. et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial. Br. J. Dermatol. 178, 114–123 (2018).

    CAS  PubMed  Google Scholar 

  106. Kobayashi, T. et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut 57, 1682–1689 (2008).

    CAS  PubMed  Google Scholar 

  107. Rovedatti, L. et al. Differential regulation of interleukin 17 and interferon γ production in inflammatory bowel disease. Gut 58, 1629–1636 (2009).

    CAS  PubMed  Google Scholar 

  108. Ochsenkuehn, T., Janelidze, S., Tillack, C. & Beigel, F. Ustekinumab as rescue treatment in therapy-refractory or -intolerant ulcerative colitis [abstract P759]. J. Crohns Colitis 12 (Suppl. 1), S495 (2018).

    Google Scholar 

  109. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02407236 (2018).

  110. Sandborn, W. J. et al. Efficacy and safety of anti-interleukin-23 therapy with mirikizumab (LY3074828) in patients with moderate-to-severe ulcerative colitis in a phase 2 study [abstract 882]. Gastroenterology 154 (Suppl. 1), S1360–S1361 (2018).

    Google Scholar 

  111. Verdier, J., Begue, B., Cerf-Bensussan, N. & Ruemmele, F. M. Compartmentalized expression of Th1 and Th17 cytokines in pediatric inflammatory bowel diseases. Inflamm. Bowel Dis. 18, 1260–1266 (2012).

    CAS  PubMed  Google Scholar 

  112. Reinisch, W. et al. A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn’s disease. Gut 55, 1138–1144 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Hommes, D. W. et al. Fontolizumab, a humanised anti-interferon gamma antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn’s disease. Gut 55, 1131–1137 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Reinisch, W. et al. Fontolizumab in moderate to severe Crohn’s disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study. Inflamm. Bowel Dis. 16, 233–242 (2010).

    PubMed  Google Scholar 

  115. Brasseit, J. et al. Divergent roles of interferon-gamma and innate lymphoid cells in innate and adaptive immune cell-mediated intestinal inflammation. Frontiers Immunol. 9, 23 (2018).

    Google Scholar 

  116. Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Targan, S. R. et al. A randomized, double-blind, placebo-controlled phase 2 study of brodalumab in patients with moderate-to-severe Crohn’s disease. Am. J. Gastroenterol. 111, 1599–1607 (2016).

    CAS  PubMed  Google Scholar 

  118. Langley, R. G. et al. Secukinumab in plaque psoriasis — results of two phase 3 trials. N. Engl. J. Med. 371, 326–338 (2014).

    PubMed  Google Scholar 

  119. Mease, P. J. et al. Secukinumab Inhibition of Interleukin-17A in patients with psoriatic arthritis. N. Engl. J. Med. 373, 1329–1339 (2015).

    CAS  PubMed  Google Scholar 

  120. Lebwohl, M. et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N. Engl. J. Med. 373, 1318–1328 (2015).

    CAS  PubMed  Google Scholar 

  121. Beringer, A., Noack, M. & Miossec, P. IL-17 in chronic inflammation: from discovery to targeting. Trends Mol. Med. 22, 230–241 (2016).

    CAS  PubMed  Google Scholar 

  122. Veldhoen, M. Interleukin 17 is a chief orchestrator of immunity. Nat. Immunol. 18, 612–621 (2017).

    CAS  PubMed  Google Scholar 

  123. Ghoreschi, K., Laurence, A., Yang, X. P., Hirahara, K. & O’Shea, J. J. T helper 17 cell heterogeneity and pathogenicity in autoimmune disease. Trends Immunol. 32, 395–401 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Yang, X. O. et al. Regulation of inflammatory responses by IL-17F. J. Exp. Med. 205, 1063–1075 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Ogawa, A., Andoh, A., Araki, Y., Bamba, T. & Fujiyama, Y. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin. Immunol. 110, 55–62 (2004).

    CAS  PubMed  Google Scholar 

  126. Fujino, S. et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52, 65–70 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Beriou, G. et al. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 113, 4240–4249 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Ueno, A. et al. Increased prevalence of circulating novel IL-17 secreting Foxp3 expressing CD4+ T cells and defective suppressive function of circulating Foxp3+ regulatory cells support plasticity between Th17 and regulatory T cells in inflammatory bowel disease patients. Inflamm. Bowel Dis. 19, 2522–2534 (2013).

    PubMed  Google Scholar 

  129. Puel, A. et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332, 65–68 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Standaert-Vitse, A. et al. Candida albicans colonization and ASCA in familial Crohn’s disease. Am. J. Gastroenterol. 104, 1745–1753 (2009).

    CAS  PubMed  Google Scholar 

  131. Leonardi, I. et al. CX3CR1+ mononuclear phagocytes control immunity to intestinal fungi. Science 359, 232–236 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Iliev, I. D. et al. Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science 336, 1314–1317 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Withers, D. R. et al. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. Nat. Med. 22, 319–323 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Shibata, A. et al. Pharmacological inhibitory profile of TAK-828F, a potent and selective orally available RORγt inverse agonist. Biochem. Pharmacol. 150, 35–45 (2018).

    CAS  PubMed  Google Scholar 

  135. Xu, M. et al. c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 554, 373–377 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Thieu, V. T. et al. Signal transducer and activator of transcription 4 is required for the transcription factor T-bet to promote T helper 1 cell-fate determination. Immunity 29, 679–690 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Fang, D. & Zhu, J. Dynamic balance between master transcription factors determines the fates and functions of CD4 T cell and innate lymphoid cell subsets. J. Exp. Med. 214, 1861–1876 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

A.R.M. researched data for the article, made substantial contributions to discussion of content, wrote the article and reviewed/edited the manuscript before submission. H.T. made substantial contributions to discussion of content and reviewed/edited the manuscript before submission. T.R. made substantial contributions to discussion of content, wrote and reviewed/edited the manuscript before submission.

Corresponding author

Correspondence to Alexander R. Moschen.

Ethics declarations

Competing interests

A.R.M. is receiving research support from AbbVie and Takeda under the framework of the Christian Doppler Research Society. He has received further consultation fees and/or speaker honoraria from AbbVie, Merck Sharp & Dohme, Takeda, Janssen-Cilag, Amgen, Sandoz and Pfizer. H.T. has received speaker honoraria from AbbVie, Janssen-Cilag, Merck Sharp & Dohme and Takeda. T.R. receives an unrestricted research grant from AbbVie, further consultation fees and/or honoraria from Abbvie, Astellas, Dr Falk, Gilead, GSK, Hospira, Janssen, MSD, Novartis, Pfizer, Sandoz and Takeda.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moschen, A.R., Tilg, H. & Raine, T. IL-12, IL-23 and IL-17 in IBD: immunobiology and therapeutic targeting. Nat Rev Gastroenterol Hepatol 16, 185–196 (2019). https://doi.org/10.1038/s41575-018-0084-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41575-018-0084-8

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing