Skip to main content
SpringerLink
Log in
Book cover

Cytokine Frontiers pp 179–198Cite as

IL-23 in Health and Disease

  • Chapter
  • First Online:

Abstract

The discovery of IL-23 and characterization of the biology governed by this cytokine has led to dramatic new insights within immunology. IL-23 is central to the pathogenesis of many immune-mediated inflammatory disorders and was shown to act via a novel IL-17-producing T helper subset, the Th17 cell. Many innate cells also respond to IL-23 and are important in both resistance to infection and in mediating autoimmune pathology. These cells are characterized by expression of RORγt transcription regulator and include subsets of γδ T cells, natural killer (NK) cells, innate lymphoid cells in the intestine and a recently described entheseal resident cell that resides at a key site for rheumatic illness. Stimulation of these various cells by IL-23 induces severe inflammation, much of which is mediated by the signature cytokines, including IL-17 and IL-22. Exploration of the biology of IL-23 has thus led to the identification of novel immune cell subsets as well as new paradigms for disease localization based upon the distribution of IL-23-responder populations. These new concepts are at the core of novel therapeutic strategies based upon neutralization of IL-23 or IL-17, which are showing encouraging results for treatment of psoriasis, multiple sclerosis, rheumatoid arthritis, and ankylosing spondylitis.

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

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

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Aggarwal S, Ghilardi N, Xie M-H, de Sauvage FJ, Gurney AL (2003) Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 278:1910–1914. doi:10.1074/jbc.M207577200

    PubMed  CAS  Google Scholar 

  • Altare F, Durandy A, Lammas D, Emile JF, Lamhamedi S, Le Deist F, Drysdale P, Jouanguy E, Döffinger R, Bernaudin F, Jeppsson O, Gollob JA, Meinl E, Segal AW, Fischer A, Kumararatne D, Casanova JL (1998a) Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 280:1432–1435

    PubMed  CAS  Google Scholar 

  • Altare F, Lammas D, Revy P, Jouanguy E, Döffinger R, Lamhamedi S, Drysdale P, Scheel-Toellner D, Girdlestone J, Darbyshire P, Wadhwa M, Dockrell H, Salmon M, Fischer A, Durandy A, Casanova JL, Kumararatne DS (1998b) Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection. J Clin Invest 102:2035–2040. doi:10.1172/JCI4950

    PubMed  CAS  Google Scholar 

  • Awasthi A, Riol-Blanco L, Jäger A, Korn T, Pot C, Galileos G, Bettelli E, Kuchroo VK, Oukka M (2009) Cutting edge: IL-23 receptor gfp reporter mice reveal distinct populations of IL-17-producing cells. J Immunol 182:5904–5908. doi:10.4049/jimmunol.0900732

    PubMed  CAS  Google Scholar 

  • Ball J (1971) Enthesopathy of rheumatoid and ankylosing spondylitis. Ann Rheum Dis 30:213–223

    PubMed  CAS  Google Scholar 

  • Ball J (1983) The enthesopathy of ankylosing spondylitis. Br J Rheumatol 22:25–28

    PubMed  CAS  Google Scholar 

  • Baraliakos X, Braun J, Laurent DD, Baeten D, van der Heijde D, Sieper J, Emery P (2011) Interleukin-17A blockade with secukinumab reduces spinal inflammation in patients with ankylosing spondylitis as early as week 6, as detected by magnetic resonance imaging. Arthritis Rheum 63(Suppl 10):2486D. doi:10.1002/(ISSN)1529-0131

    Google Scholar 

  • Becher B, Durell BG, Noelle RJ (2002) Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest 110:493–497. doi:10.1172/JCI15751

    PubMed  CAS  Google Scholar 

  • Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature (Lond) 441:235–238. doi:10.1038/nature04753

    CAS  Google Scholar 

  • Billiau A, Heremans H, Vandekerckhove F, Dijkmans R, Sobis H, Meulepas E, Carton H (1988) Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-gamma. J Immunol 140:1506–1510

    PubMed  CAS  Google Scholar 

  • Bowness P, Ridley A, Shaw J, Chan AT, Wong-Baeza I, Fleming M, Cummings F, McMichael A, Kollnberger S (2011) Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis. J Immunol 186:2672–2680. doi:10.4049/jimmunol.1002653

    PubMed  CAS  Google Scholar 

  • Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR, Maloy KJ, Powrie F (2010) Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature (Lond) 464:1371–1375. doi:10.1038/nature08949

    CAS  Google Scholar 

  • Cai Y, Shen X, Ding C, Qi C, Li K, Li X, Jala VR, Zhang H-G, Wang T, Zheng J, Yan J (2011) Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity 35:596–610. doi:10.1016/j.immuni.2011.08.001

    PubMed  CAS  Google Scholar 

  • Capon F, Di Meglio P, Szaub J, Prescott NJ, Dunster C, Baumber L, Timms K, Gutin A, Abkevic V, Burden AD, Lanchbury J, Barker JN, Trembath RC, Nestle FO (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. doi:10.1007/s00439-007-0397-0

    PubMed  CAS  Google Scholar 

  • Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KP, Matsunami N, Ardlie KG, Civello D, Catanese JJ, Leong DU, Panko JM, McAllister LB, Hansen CB, Papenfuss J, Prescott SM, White TJ, Leppert MF, Krueger GG, Begovich AB (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. doi:10.1086/511051

    PubMed  CAS  Google Scholar 

  • Cella M, Fuchs A, Vermi W, Facchetti F, Otero K, Lennerz JKM, Doherty JM, Mills JC, Colonna M (2009) A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature (Lond) 457:722–725. doi:10.1038/nature07537

    CAS  Google Scholar 

  • Chan JR, Blumenschein W, Murphy E, Diveu C, Wiekowski M, Abbondanzo S, Lucian L, Geissler R, Brodie S, Kimball AB, Gorman DM, Smith K, de Waal-Malefyt R, Kastelein RA, McClanahan TK, Bowman EP (2006) IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med 203:2577–2587. doi:10.1084/jem.20060244

    PubMed  CAS  Google Scholar 

  • Ciccia F, Bombardieri M, Principato A, Giardina A, Tripodo C, Porcasi R, Peralta S, Franco V, Giardina E, Craxi A, Pitzalis C, Triolo G (2009) Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. Arthritis Rheum 60:955–965. doi:10.1002/art.24389

    PubMed  CAS  Google Scholar 

  • Codarri L, Gyülvészi G, Tosevski V, Hesske L, Fontana A, Magnenat L, Suter T, Becher B (2011) RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12:560–567. doi:10.1038/ni.2027

    PubMed  CAS  Google Scholar 

  • Colbert RA, DeLay ML, Klenk EI, Layh-Schmitt G (2010) From HLA-B27 to spondyloarthritis: a journey through the ER. Immunol Rev 233:181–202. doi:10.1111/j.0105-2896.2009.00865.x

    PubMed  CAS  Google Scholar 

  • Crellin NK, Trifari S, Kaplan CD, Cupedo T, Spits H (2010) Human NKp44+IL-22+ cells and LTi-like cells constitute a stable RORC+ lineage distinct from conventional natural killer cells. J Exp Med 207:281–290. doi:10.1084/jem.20091509

    PubMed  CAS  Google Scholar 

  • Cua DJ, Sherlock JP (2011) Autoimmunity’s collateral damage: gut microbiota strikes ‘back’. Nat Med 17:1055–1056. doi:10.1038/nm0911-1055

    PubMed  CAS  Google Scholar 

  • Cua DJ, Sherlock JP, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature (Lond) 421:744–748. doi:10.1038/nature01355

    CAS  Google Scholar 

  • Cui Y, Shao H, Lan C, Nian H, O’Brien RL, Born WK, Kaplan HJ, Sun D (2009) Major role of gamma delta T cells in the generation of IL-17+ uveitogenic T cells. J Immunol 183:560–567. doi:10.4049/jimmunol.0900241

    PubMed  CAS  Google Scholar 

  • Cupedo T, Crellin NK, Papazian N, Rombouts EJ, Weijer K, Grogan JL, Fibbe WE, Cornelissen JJ, Spits H (2009) Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nat Immunol 10:66–74. doi:10.1038/ni.1668

    PubMed  CAS  Google Scholar 

  • DeLay ML, Turner MJ, Klenk EI, Smith JA, Sowders DP, Colbert RA (2009) HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats. Arthritis Rheum 60:2633–2643. doi:10.1002/art.24763

    PubMed  CAS  Google Scholar 

  • Duan J, Chung H, Troy E, Kasper DL (2010) Microbial colonization drives expansion of IL-1 receptor 1-expressing and IL-17-producing gamma/delta T cells. Cell Host Microbe 7:140–150. doi:10.1016/j.chom.2010.01.005

    PubMed  CAS  Google Scholar 

  • Duong TT, St. Louis J, Gilbert JJ, Finkelman FD, Strejan GH (1992) Effect of anti-interferon-gamma and anti-interleukin-2 monoclonal antibody treatment on the development of actively and passively induced experimental allergic encephalomyelitis in the SJL/J mouse. J Neuroimmunol 36:105–115

    PubMed  CAS  Google Scholar 

  • Dupuis S, Dargemont C, Fieschi C, Thomassin N, Rosenzweig S, Harris J, Holland SM, Schreiber RD, Casanova JL (2001) Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science 293:300–303. doi:10.1126/science.1061154

    PubMed  CAS  Google Scholar 

  • El-Behi M, Ciric B, Dai H, Yan Y, Cullimore M, Safavi F, Zhang G-X, Dittel BN, Rostami A (2011) The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol 12:568–575. doi:10.1038/ni.2031

    PubMed  CAS  Google Scholar 

  • Fenoglio D, Poggi A, Catellani S, Battaglia F, Ferrera A, Setti M, Murdaca G, Zocchi MR (2009) Vdelta1 T lymphocytes producing IFN-gamma and IL-17 are expanded in HIV-1-infected patients and respond to Candida albicans. Blood 113:6611–6618. doi:10.1182/blood-2009-01-198028

    PubMed  CAS  Google Scholar 

  • Ferber IA, Brocke S, Taylor-Edwards C, Ridgway W, Dinisco C, Steinman L, Dalton D, Fathman CG (1996) Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol 156:5–7

    PubMed  CAS  Google Scholar 

  • Ghoreschi K, Laurence A, Yang X-P, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun H-W, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O’Shea JJ (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling. Nature (Lond) 467:967–971. doi:10.1038/nature09447

    CAS  Google Scholar 

  • Goodall JC, Wu C, Zhang Y, McNeill L, Ellis L, Saudek V, Gaston JSH (2010) Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. Proc Natl Acad Sci USA 107:17698–17703. doi:10.1073/pnas.1011736107

    PubMed  CAS  Google Scholar 

  • Gottlieb A, Menter A, Mendelsohn A, Shen Y-K, Li S, Guzzo C, Fretzin S, Kunynetz R, Kavanaugh A (2009) Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet 373:633–640. doi:10.1016/S0140-6736(09)60140-9

    PubMed  CAS  Google Scholar 

  • Haas JD, González FHM, Schmitz S, Chennupati V, Föhse L, Kremmer E, Förster R, Prinz I (2009) CCR6 and NK1.1 distinguish between IL-17A and IFN-gamma-producing gammadelta effector T cells. Eur J Immunol 39:3488–3497. doi:10.1002/eji.200939922

    PubMed  CAS  Google Scholar 

  • Happel KI, Zheng M, Young E, Quinton LJ, Lockhart E, Ramsay AJ, Shellito JE, Schurr JR, Bagby GJ, Nelson S, Kolls JK (2003) Cutting edge: roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection. J Immunol 170:4432–4436

    PubMed  CAS  Google Scholar 

  • Happel KI, Dubin PJ, Zheng M, Ghilardi N, Lockhart C, Quinton LJ, Odden AR, Shellito JE, Bagby GJ, Nelson S, Kolls JK (2005) Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J Exp Med 202:761–769. doi:10.1084/jem.20050193

    PubMed  CAS  Google Scholar 

  • Hayday AC (2000) γδ cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol 18:975–1026. doi:10.1146/annurev.immunol.18.1.975

    PubMed  CAS  Google Scholar 

  • Heremans H, Dillen C, Groenen M, Martens E, Billiau A (1996) Chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice: enhancement by monoclonal antibodies against interferon-gamma. Eur J Immunol 26:2393–2398. doi:10.1002/eji.1830261019

    PubMed  CAS  Google Scholar 

  • Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, Freeman AF, Demidowich A, Davis J, Turner ML, Anderson VL, Darnell DN, Welch PA, Kuhns DB, Frucht DM, Malech HL, Gallin JI, Kobayashi SD, Whitney AR, Voyich JM, Musser JM, Woellner C, Schäffer AA, Puck JM, Grimbacher B (2007) STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 357:1608–1619. doi:10.1056/NEJMoa073687

    PubMed  CAS  Google Scholar 

  • Huang W, Na L, Fidel PL, Schwarzenberger P (2004) Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis 190:624–631. doi:10.1086/422329

    PubMed  CAS  Google Scholar 

  • Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, Antoni C, Draelos Z, Gold MH, Psoriasis Study Group, Durez P, Tak PP, Gomez-Reino JJ, Rheumatoid Arthritis Study Group, Foster CS, Kim RY, Samson CM, Falk NS, Chu DS, Callanan D, Nguyen QD, Uveitis Study Group, Rose K, Haider A, Di Padova F (2010) Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med 2:52ra72. doi:10.1126/scitranslmed.3001107

    PubMed  Google Scholar 

  • Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PDR, Wehkamp J, Feagan BG, Yao MD, Karczewski M, Karczewski J, Pezous N, Bek S, Bruin G, Mellgard B, Berger C, Londei M, Bertolino AP, Tougas G, Travis SPL, for the Secukinumab in Crohn’s Disease Study Group (2012) 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. doi:10.1136/gutjnl-2011-301668

    PubMed  CAS  Google Scholar 

  • Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133. doi:10.1016/j.cell.2006.07.035

    PubMed  CAS  Google Scholar 

  • Jensen KDC, Su X, Shin S, Li L, Youssef S, Yamasaki S, Steinman L, Saito T, Locksley RM, Davis MM, Baumgarth N, Chien Y-H (2008) Thymic selection determines gammadelta T cell effector fate: antigen-naive cells make interleukin-17 and antigen-experienced cells make interferon gamma. Immunity 29:90–100. doi:10.1016/j.immuni.2008.04.022

    PubMed  CAS  Google Scholar 

  • Jones SA, Sutton CE, Cua DJ, Mills KHG (2012) Therapeutic potential of targeting IL-17. Nat Immunol 13:1022–1025. doi:10.1038/ni.2450

    PubMed  CAS  Google Scholar 

  • Jouanguy E, Altare F, Lamhamedi S, Revy P, Emile JF, Newport M, Levin M, Blanche S, Seboun E, Fischer A, Casanova JL (1996) Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guérin infection. N Engl J Med 335:1956–1961. doi:10.1056/NEJM199612263352604

    PubMed  CAS  Google Scholar 

  • Korn T, Bettelli E, Gao W, Awasthi A, Jäger A, Strom TB, Oukka M, Kuchroo VK (2007) IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature (Lond) 448:484–487. doi:10.1038/nature05970

    CAS  Google Scholar 

  • Krueger GG, Langley RG, Leonardi C, Yeilding N, Guzzo C, Wang Y, Dooley LT, Lebwohl M, CNTO 1275 Psoriasis Study Group (2007) A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 356:580–592. doi:10.1056/NEJMoa062382

    PubMed  CAS  Google Scholar 

  • Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, Dhodapkar M, Krueger JG (2004) Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med 199:125–130. doi:10.1084/jem.20030451

    PubMed  CAS  Google Scholar 

  • Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, Wu C, Kleinewietfeld M, Kunder S, Hafler DA, Sobel RA, Regev A, Kuchroo VK (2012) Induction and molecular signature of pathogenic T(H)17 cells. Nat Immunol 13:991–999. doi:10.1038/ni.2416

    PubMed  CAS  Google Scholar 

  • Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, Li S, Dooley LT, Gordon KB, 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, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371:1665–1674. doi:10.1016/S0140-6736(08)60725-4

    PubMed  CAS  Google Scholar 

  • Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, Braun D, Banerjee S (2012) Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 366:1190–1199. doi:10.1056/NEJMoa1109997

    PubMed  CAS  Google Scholar 

  • Lockhart E, Green AM, Flynn JL (2006) IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J Immunol 177:4662–4669

    PubMed  CAS  Google Scholar 

  • Lublin FD, Knobler RL, Kalman B, Goldhaber M, Marini J, Perrault M, D’Imperio C, Joseph J, Alkan SS, Korngold R (1993) Monoclonal anti-gamma interferon antibodies enhance experimental allergic encephalomyelitis. Autoimmunity 16:267–274

    PubMed  CAS  Google Scholar 

  • Luci C, Reynders A, Ivanov II, Cognet C, Chiche L, Chasson L, Hardwigsen J, Anguiano E, Banchereau J, Chaussabel D, Dalod M, Littman DR, Vivier E, Tomasello E (2009) Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin. Nat Immunol 10:75–82. doi:10.1038/ni.1681

    PubMed  CAS  Google Scholar 

  • Ma CS, Chew GYJ, Simpson N, Priyadarshi A, Wong M, Grimbacher B, Fulcher DA, Tangye SG, Cook MC (2008) Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med 205:1551–1557. doi:10.1084/jem.20080218

    PubMed  CAS  Google Scholar 

  • Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature (Lond) 441:231–234. doi:10.1038/nature04754

    CAS  Google Scholar 

  • Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M (2009) Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity 31:321–330. doi:10.1016/j.immuni.2009.06.020

    PubMed  CAS  Google Scholar 

  • McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM, McClanahan TK, O’Shea JJ, Cua DJ (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. doi:10.1038/ni.1698

    PubMed  CAS  Google Scholar 

  • McGonagle D, Gibbon W, Emery P (1998) Classification of inflammatory arthritis by enthesitis. Lancet 352:1137–1140. doi:10.1016/S0140-6736(97)12004-9

    PubMed  CAS  Google Scholar 

  • Mielants H, Veys EM, Cuvelier C, de Vos M, Goemaere S, de Clercq L, Schatteman L, Elewaut D (1995) The evolution of spondyloarthropathies in relation to gut histology. II. Histological aspects. J Rheumatol 22:2273–2278

    PubMed  CAS  Google Scholar 

  • Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, Davis J, Hsu A, Asher AI, O’Shea J, Holland SM, Paul WE, Douek DC (2008) Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature (Lond) 452:773–776. doi:10.1038/nature06764

    CAS  Google Scholar 

  • Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O, Metin A, Karasuyama H (2007) Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448:1058–1062. doi:10.1038/nature06096

    PubMed  CAS  Google Scholar 

  • Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348–2357

    PubMed  CAS  Google Scholar 

  • Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ (2003) Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 198:1951–1957. doi:10.1084/jem.20030896

    PubMed  CAS  Google Scholar 

  • Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, Gudjonsson JE, Li Y, Tejasvi T, Feng B-J, Ruether A, Schreiber S, Weichenthal M, Gladman D, Rahman P, Schrodi SJ, Prahalad S, Guthery SL, Fischer J, Liao W, Kwok P-Y, Menter A, Lathrop GM, Wise CA, Begovich AB, Voorhees JJ, Elder JT, Krueger GG, Bowcock AM, Abecasis GR, Collaborative Association Study of Psoriasis (2009) Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet 41:199–204. doi:10.1038/ng.311

    PubMed  CAS  Google Scholar 

  • Newport MJ, Huxley CM, Huston S, Hawrylowicz CM, Oostra BA, Williamson R, Levin M (1996) A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med 335:1941–1949. doi:10.1056/NEJM199612263352602

    PubMed  CAS  Google Scholar 

  • Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA (2000) 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

    PubMed  CAS  Google Scholar 

  • Papp KA, Leonardi C, Menter A, Ortonne J-P, Krueger JG, Kricorian G, Aras G, Li J, Russell CB, Thompson EHZ, Baumgartner S (2012) Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med 366:1181–1189. doi:10.1056/NEJMoa1109017

    PubMed  CAS  Google Scholar 

  • Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F, To W, Wagner J, O’Farrell A-M, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein RA, de Waal MR, Moore KW (2002) 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

    PubMed  CAS  Google Scholar 

  • Peng MY, Wang ZH, Yao CY, Jiang LN, Jin QL, Wang J, Li BQ (2008) Interleukin 17-producing gamma delta T cells increased in patients with active pulmonary tuberculosis. Cell Mol Immunol 5:203–208. doi:10.1038/cmi.2008.25

    PubMed  Google Scholar 

  • Piskin G, Sylva-Steenland RMR, Bos JD, Teunissen MBM (2006) In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol 176:1908–1915

    PubMed  CAS  Google Scholar 

  • Reich K, Langley RG, Papp KA, Ortonne J-P, Unnebrink K, Kaul M, Valdes JM (2011) A 52-week trial comparing briakinumab with methotrexate in patients with psoriasis. N Engl J Med 365:1586–1596. doi:10.1056/NEJMoa1010858

    PubMed  CAS  Google Scholar 

  • Reveille JD, Sims A-M, Danoy P, Evans DM, Leo P, Pointon JJ, Jin R, Zhou X, Bradbury LA, Appleton LH, Davis JC, Diekman L, Doan T, Dowling A, Duan R, Duncan EL, Farrar C, Hadler J, Harvey D, Karaderi T, Mogg R, Pomeroy E, Pryce K, Taylor J, Savage L, Deloukas P, Kumanduri V, Peltonen L, Ring SM, Whittaker P, Glazov E, Thomas GP, Maksymowych WP, Inman RD, Ward MM, Stone MA, Weisman MH, Wordsworth BP, Brown MA (2010) Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 42:123–127. doi:10.1038/ng.513

    PubMed  CAS  Google Scholar 

  • Ribot JC, deBarros A, Pang DJ, Neves JF, Peperzak V, Roberts SJ, Girardi M, Borst J, Hayday AC, Pennington DJ, Silva-Santos B (2009) CD27 is a thymic determinant of the balance between interferon-gamma- and interleukin 17-producing gammadelta T cell subsets. Nat Immunol 10:427–436. doi:10.1038/ni.1717

    PubMed  CAS  Google Scholar 

  • Roark CL, French JD, Taylor MA, Bendele AM, Born WK, O’Brien RL (2007) Exacerbation of collagen-induced arthritis by oligoclonal, IL-17-producing gamma delta T cells. J Immunol 179:5576–5583

    PubMed  CAS  Google Scholar 

  • Sandborn WJ, Gasink C, Gao L-L, Blank MA, Johanns J, Guzzo C, Sands BE, Hanauer SB, Targan S, Rutgeerts P, Ghosh S, de Villiers WJS, Panaccione R, Greenberg G, Schreiber S, Lichtiger S, Feagan BG, CERTIFI Study Group (2012) Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N Engl J Med 367:1519–1528. doi:10.1056/NEJMoa1203572

    PubMed  CAS  Google Scholar 

  • Sanos SL, Bui VL, Mortha A, Oberle K, Heners C, Johner C, Diefenbach A (2009) RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat Immunol 10:83–91. doi:10.1038/ni.1684

    PubMed  CAS  Google Scholar 

  • Satoh-Takayama N, Vosshenrich CAJ, Lesjean-Pottier S, Sawa S, Lochner M, Rattis F, Mention J-J, Thiam K, Cerf-Bensussan N, Mandelboim O, Eberl G, Di Santo JP (2008) Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29:958–970. doi:10.1016/j.immuni.2008.11.001

    PubMed  CAS  Google Scholar 

  • Segal BM, Dwyer BK, Shevach EM (1998) An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J Exp Med 187:537–546

    PubMed  CAS  Google Scholar 

  • Sherlock JP, Joyce-Shaikh B, Turner SP, Chao C-C, Sathe M, Grein J, Gorman DM, Bowman EP, McClanahan TK, Yearley JH, Eberl G, Buckley CD, Kastelein RA, Pierce RH, LaFace DM, Cua DJ (2012) IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4-CD8- entheseal resident T cells. Nat Med 18:1069–1076. doi:10.1038/nm.2817

    PubMed  CAS  Google Scholar 

  • Shibata K, Yamada H, Hara H, Kishihara K, Yoshikai Y (2007) Resident Vdelta1+ gammadelta T cells control early infiltration of neutrophils after Escherichia coli infection via IL-17 production. J Immunol 178:4466–4472

    PubMed  CAS  Google Scholar 

  • Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KHG (2009) Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 31:331–341. doi:10.1016/j.immuni.2009.08.001

    PubMed  CAS  Google Scholar 

  • Takatori H, Kanno Y, Watford WT, Tato CM, Weiss G, Ivanov II, Littman DR, O’Shea JJ (2009) Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J Exp Med 206:35–41. doi:10.1084/jem.20072713

    PubMed  CAS  Google Scholar 

  • Taurog JD, Rival C, van Duivenvoorde LM, Satumtira N, Dorris ML, Sun M, Shelton JM, Richardson JA, Hamra FK, Hammer RE, Tung KSK (2012) Autoimmune epididymoorchitis is essential to the pathogenesis of male-specific spondylarthritis in HLA-B27-transgenic rats. Arthritis Rheum 64:2518–2528. doi:10.1002/art.34480

    PubMed  CAS  Google Scholar 

  • Tonel G, Conrad C, Laggner U, Di Meglio P, Grys K, McClanahan TK, Blumenschein WM, Qin J-Z, Xin H, Oldham E, Kastelein RA, Nickoloff BJ, Nestle FO (2010) Cutting edge: a critical functional role for IL-23 in psoriasis. J Immunol 185:5688–5691. doi:10.4049/jimmunol.1001538

    PubMed  CAS  Google Scholar 

  • Uhlig HH, McKenzie BS, Hue S, Thompson C, Joyce-Shaikh B, Stepankova R, Robinson N, Buonocore S, Tlaskalova-Hogenova H, Cua DJ, Powrie F (2006) Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25:309–318. doi:10.1016/j.immuni.2006.05.017

    PubMed  CAS  Google Scholar 

  • Umemura M, Yahagi A, Hamada S, Begum MD, Watanabe H, Kawakami K, Suda T, Sudo K, Nakae S, Iwakura Y, Matsuzaki G (2007) IL-17-mediated regulation of innate and acquired immune response against pulmonary Mycobacterium bovis bacille Calmette-Guerin infection. J Immunol 178:3786–3796

    PubMed  CAS  Google Scholar 

  • Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006a) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189. doi:10.1016/j.immuni.2006.01.001

    PubMed  CAS  Google Scholar 

  • Veldhoen M, Hocking RJ, Flavell RA, Stockinger B (2006b) Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol 7:1151–1156. doi:10.1038/ni1391

    PubMed  CAS  Google Scholar 

  • Voorthuis JA, Uitdehaag BM, De Groot CJ, Goede PH, van der Meide PH, Dijkstra CD (1990) Suppression of experimental allergic encephalomyelitis by intraventricular administration of interferon-gamma in Lewis rats. Clin Exp Immunol 81:183–188

    PubMed  CAS  Google Scholar 

  • Wellcome Trust Case Control Consortium, Australo-Anglo-American Spondylitis Consortium (TASC), Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, Ouwehand WH, Samani NJ, Todd JA, Donnelly P, Barrett JC, Davison D, Easton D, Evans DM, Leung H-T, Marchini JL, Morris AP, Spencer CCA, Tobin MD, Attwood AP, Boorman JP, Cant B, Everson U, Hussey JM, Jolley JD, Knight AS, Koch K, Meech E, Nutland S, Prowse CV, Stevens HE, Taylor NC, Walters GR, Walker NM, Watkins NA, Winzer T, Jones RW, McArdle WL, Ring SM, Strachan DP, Pembrey M, Breen G, St Clair D, Caesar S, Gordon-Smith K, Jones L, Fraser C, Green EK, Grozeva D, Hamshere ML, Holmans PA, Jones IR, Kirov G, Moskivina V, Nikolov I, O'Donovan MC, Owen MJ, Collier DA, Elkin A, Farmer A, Williamson R, McGuffin P, Young AH, Ferrier IN, Ball SG, Balmforth AJ, Barrett JH, Bishop TD, Iles MM, Maqbool A, Yuldasheva N, Hall AS, Braund PS, Dixon RJ, Mangino M, Stevens S, Thompson JR, Bredin F, Tremelling M, Parkes M, Drummond H, Lees CW, Nimmo ER, Satsangi J, Fisher SA, Forbes A, Lewis CM, Onnie CM, Prescott NJ, Sanderson J, Matthew CG, Barbour J, Mohiuddin MK, Todhunter CE, Mansfield JC, Ahmad T, Cummings FR, Jewell DP, Webster J, Brown MJ, Lathrop MG, Connell J, Dominiczak A, Marcano CA, Burke B, Dobson R, Gungadoo J, Lee KL, Munroe PB, Newhouse SJ, Onipinla A, Wallace C, Xue M, Caulfield M, Farrall M, Barton A, Biologics in RA Genetics and Genomics Study Syndicate (BRAGGS) Steering Committee, Bruce IN, Donovan H, Eyre S, Gilbert PD, Hilder SL, Hinks AM, John SL, Potter C, Silman AJ, Symmons DP, Thomson W, Worthington J, Dunger DB, Widmer B, Frayling TM, Freathy RM, Lango H, Perry JR, Shields BM, Weedon MN, Hattersley AT, Hitman GA, Walker M, Elliott KS, Groves CJ, Lindgren CM, Rayner NW, Timpson NJ, Zeggini E, Newport M, Sirugo G, Lyons E, Vannberg F, Hill AV, Bradbury LA, Farrar C, Pointon JJ, Wordsworth P, Brown MA, Franklyn JA, Heward JM, Simmonds MJ, Gough SC, Seal S, Breast Cancer Susceptibility Collaboration (UK), Stratton MR, Rahman N, Ban M, Goris A, Sawcer SJ, Compston A, Conway D, Jallow M, Newport M, Sirugo G, Rockett KA, Bumpstead SJ, Chaney A, Downes K, Ghori MJ, Gwilliam R, Hunt SE, Inouye M, Keniry A, King E, McGinnis R, Potter S, Ravindrarajah R, Whittaker P, Widden C, Withers D, Cardin NJ, Davison D, Ferreira T, Pereira-Gale J, Hallgrimsdo'ttir IB, Howie BN, Su Z, Teo YY, Vukcevic D, Bentley D, Brown MA, Compston A, Farrall M, Hall AS, Hattersley AT, Hill AV, Parkes M, Pembrey M, Stratton MR, Mitchell SL, Newby PR, Brand OJ, Carr-Smith J, Pearce SH, McGinnis R, Keniry A, Deloukas P, Reveille JD, Zhou X, Sims AM, Dowling A, Taylor J, Doan T, Davis JC, Savage L, Ward MM, Learch TL, Weisman MH, Brown M (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39:1329–1337. doi:10.1038/ng.2007.17

    PubMed  CAS  Google Scholar 

  • Willenborg DO, Fordham S, Bernard CC, Cowden WB, Ramshaw IA (1996) IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J Immunol 157:3223–3227

    PubMed  CAS  Google Scholar 

  • Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282:9358–9363. doi:10.1074/jbc.C600321200

    PubMed  CAS  Google Scholar 

  • Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, Kleinschek MA, Owyang A, Mattson J, Blumenschein W, Murphy E, Sathe M, Cua DJ, Kastelein RA, Rennick D (2006) IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 116:1310–1316. doi:10.1172/JCI21404

    PubMed  CAS  Google Scholar 

  • Zeng R, Spolski R, Casas E, Zhu W, Levy DE, Leonard WJ (2007) The molecular basis of IL-21-mediated proliferation. Blood 109:4135–4142. doi:10.1182/blood-2006-10-054973

    PubMed  CAS  Google Scholar 

  • Zhang G-X, Gran B, Yu S, Li J, Siglienti I, Chen X, Kamoun M, Rostami A (2003) Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-beta 2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system. J Immunol 170:2153–2160

    PubMed  CAS  Google Scholar 

  • Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, Ouyang W (2007) Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature (Lond) 445:648–651. doi:10.1038/nature05505

    CAS  Google Scholar 

  • Zúñiga LA, Jain R, Haines C, Cua DJ (2013) Th17 cell development: from the cradle to the grave. Immunol Rev 252:78–88. doi:10.1111/imr.12036

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre for Translational Inflammation Research, University of Birmingham, Birmingham, 15 2TT, UK

    Jonathan P. Sherlock

  2. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, 3 7HE, UK

    Jonathan P. Sherlock

  3. Merck Research Labs, 901 S. California Ave, Palo Alto, CA, 94304, USA

    Luis A. Zuniga & Daniel J. Cua

Authors
  1. Jonathan P. Sherlock
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luis A. Zuniga
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel J. Cua
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel J. Cua .

Editor information

Editors and Affiliations

  1. Department of Immunoregulation Institute of Medical Science, Tokyo Medical University, Tokyo, Tokyo, Japan

    Takayuki Yoshimoto

  2. Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan

    Tomohiro Yoshimoto

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Japan

About this chapter

Cite this chapter

Sherlock, J.P., Zuniga, L.A., Cua, D.J. (2014). IL-23 in Health and Disease. In: Yoshimoto, T., Yoshimoto, T. (eds) Cytokine Frontiers. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54442-5_7

Download citation

Publish with us

Policies and ethics

Search

Navigation