Skip to main content
SpringerLink
Log in

Interleukin-15

  • Chapter
New Therapeutic Targets in Rheumatoid Arthritis

Part of the book series: Progress in Inflammation Research ((PIR))

  • 804 Accesses

Abstract

Interleukin-15 (IL-15) is a cytokine of the four-α-helix superfamily that mediates pleiotropic effects in regulating components of both the innate and adaptive immune system. It binds to a heterotrimeric receptor consisting of the common γ-chain receptor, IL-15/IL-2 receptor β-chain and unique IL-15 receptor α-chain. IL-15 is expressed at the mRNA level in a variety of cell lineages and is expressed as protein as part of the rapid early inflammatory response. It mediates activation of NK cells, T cells, neutrophils and macrophages and as such is considered a broad immune activating moiety. IL-15 expression has been described in a variety of inflammatory diseases, including particularly rheumatoid arthritis, psoriatic arthritis and reactive arthritis. Within synovial tissues in particular it has been ascribed an inflammatory role by virtue of its capacity to activate T cells, NK cells macrophages and neutrophils. Moreover, in vivo model studies suggest that IL-15 neutralisation leads to reduction in articular inflammation and damage. Early clinical trials have shown promise in that IL-15 blockade using a monoclonal antibody in rheumatoid arthritis patients lead to some trends to improvement, providing biological proof of concept.

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

Access this chapter

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 229.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 289.00
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

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Grabstein KH, Eisenman J, Shanebeck K, Rauch C et al (1994) Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science 264: 965–968

    Article  PubMed  CAS  Google Scholar 

  2. Bamford R, Grant A, Burton J, Peters C et al (1994) The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci USA 91: 4940–4944

    Article  PubMed  CAS  Google Scholar 

  3. Waldmann TA, Tagaya Y (1999) The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens. Annu Rev Immunol 17: 19–49

    Article  PubMed  CAS  Google Scholar 

  4. Budagian V, Bulanova E, Paus R, Bulfone-Paus S (2006) IL-15/IL-15 receptor biology: A guided tour through an expanding universe. Cytokine Growth Factor Rev 17: 259–280

    Article  PubMed  CAS  Google Scholar 

  5. Bamford RN, DeFilippis AP, Azimi N, Kurys G et al (1998) The 5′ untranslated region, signal peptide, and the coding sequence of the carboxyl terminus of IL-15 participate in its multifaceted translational control. J Immunol 160: 4418–4426

    PubMed  CAS  Google Scholar 

  6. Tagaya Y, Kurys G, Thies TA, Losi JM et al (1997) Generation of secretable and nonsecretable interleukin-15 isoforms through alternate usage of signal peptides. Proc Natl Acad Sci USA 94: 14444–14449

    Article  PubMed  CAS  Google Scholar 

  7. Nishimura H, Washizu J, Nakamura N, Enomoto A et al (1998) Translational Efficiency Is up-regulated by alternative exon in murine IL-15 mRNA. J Immunol 160: 936–942

    PubMed  CAS  Google Scholar 

  8. Gaggero A, Azzarone B, Andrei C, Mishal Z et al (1999) Differential intracellular trafficking, secretion and endosomal localization of two IL-15 isoforms. Eur J Immunol 29: 1265–1274

    Article  PubMed  CAS  Google Scholar 

  9. Nishimura H, Fujimoto A, Tamura N, Yajima T et al (2005) A novel autoregulatory mechanism for transcriptional activation of the IL-15 gene by a nonsecretable isoform of IL-15 generated by alternative splicing. FASEB J 19: 19–28

    Article  PubMed  CAS  Google Scholar 

  10. Dubois S, Magrangeas F, Lehours P, Raher S et al (1999) Natural splicing of exon 2 of human interleukin-15 receptor α chain mRNA results in shortened form with a distinct pattern of expression. J Biol Chem 274: 26978–84

    Article  PubMed  CAS  Google Scholar 

  11. Waldmann T, Tagaya Y, Bamford R (1998) Interleukin-2, interleukin-15, and their receptors. Int Rev Immunol 16: 205–226

    Article  PubMed  CAS  Google Scholar 

  12. Tagaya Y, Bamford RN, DeFilippis AP, Waldmann TA (1996) IL-15: A pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels. Immunity 4: 329–336

    Article  PubMed  CAS  Google Scholar 

  13. Dubois S, Magrangeas F, Lehours P, Raher S et al (1999) Natural splicing of exon 2 of human interleukin-15 receptor α chain mRNA results in shortened form with a distinct pattern of expression. J Biol Chem 274: 26978–26984

    Article  PubMed  CAS  Google Scholar 

  14. Budagian V, Bulanova E, Orinska Z, Thon L et al (2005) A promiscuous liaison between IL-15 receptor and Axl receptor tyrosine kinase in cell death control. EMBO J 24: 4260–70

    Article  PubMed  CAS  Google Scholar 

  15. Dubois S, Mariner J, Waldmann TA, Tagaya Y (2002) IL-15Ra recycles and presents IL-15 in trans to neighboring cells. Immunity 17: 537–47

    Article  PubMed  CAS  Google Scholar 

  16. Budagian V, Bulanova E, Orinska Z, Pohl T et al (2004) Reverse signaling through membrane-bound interleukin-15. J Biol Chem 279: 42192–201

    Article  PubMed  CAS  Google Scholar 

  17. Neely GG, Epelman S, Ma LL, Colarusso P, Howlett CJ, Amankwah EK et al (2004) Monocytes surface-bound IL-15 can function as an activating receptor and participate in reverse signaling. J Immunol 172: 4225–34

    PubMed  CAS  Google Scholar 

  18. Nishimura H, Hiromatsu K, Kobayashi N, Grabstein KH et al (1996) IL-15 is a novel growth factor for murine gamma delta T cells induced by Salmonella infection. J Immunol 156: 663–669

    PubMed  CAS  Google Scholar 

  19. Korholz D, Banning U, Bonig H, Grewe M et al (1997) The role of interleukin-10 (IL-10) in IL-15-mediated T-cell responses. Blood 90: 4513–4521

    PubMed  CAS  Google Scholar 

  20. Kanegane H, Tosato G (1996) Activation of naive and memory T cells by interleukin-15. Blood 88: 230–235

    PubMed  CAS  Google Scholar 

  21. Mottonen M, Isomaki P, Luukkainen R, Toivanen P et al (2000) Interleukin-15 up-regulates the expression of CD154 on synovial fluid T cells. Immunology 100: 238–244

    Article  PubMed  CAS  Google Scholar 

  22. Wilkinson PC, Liew FY (1995) Chemoattraction of human blood T lymphocytes by interleukin-15. J Exp Med 181: 1255–1259

    Article  PubMed  CAS  Google Scholar 

  23. Al-Mughales J, Blyth TH, Hunter JA, Wilkinson PC (1996) The chemoattractant activity of rheumatoid synovial fluid for human lymphocytes is due to multiple cytokines. Clin Exp Immunol 106: 230–236

    Article  PubMed  CAS  Google Scholar 

  24. Nieto M, del Pozo MA, Sanchez-Madrid F (1996) Interleukin-15 induces adhesion receptor redistribution in T lymphocytes. Eur J Immunol 26: 1302–1307

    Article  PubMed  CAS  Google Scholar 

  25. Seder RA, Grabstein KH, Berzofsky JA, McDyer JF (1995) Cytokine interactions in human immunodeficiency virus-infected individuals: Roles of interleukin (IL)-2, IL-12, and IL-15. J Exp Med 182: 1067–1077

    Article  PubMed  CAS  Google Scholar 

  26. Mori A, Suko M, Kaminuma O, Inoue S et al (1996) IL-15 promotes cytokine production of human T helper cells. J Immunol 156: 2400–2405

    PubMed  CAS  Google Scholar 

  27. Tough DF, Zhang X, Sprent J (2001) An IFN-gamma-dependent pathway controls stimulation of memory phenotype CD8+ T cell turnover in vivo by IL-12, IL-18, and IFN-gamma. J Immunol 166: 6007–6011

    PubMed  CAS  Google Scholar 

  28. Yajima T, Nishimura H, Ishimitsu R, Watase T et al (2002) Overexpression of IL-15 in vivo increases antigen-driven memory CD8+ T cells following a microbe exposure. J Immunol 168: 1198–1203

    PubMed  CAS  Google Scholar 

  29. Geginat J, Sallusto F, Lanzavecchia A (2001) Cytokine-driven proliferation and differentiation of human naive, central memory, and effector memory CD4+ T cells. J Exp Med 194: 1711–1720

    Article  PubMed  CAS  Google Scholar 

  30. Niedbala W, Wei X, Liew FY (2002) IL-15 induces type 1 and type 2 CD4+ and CD8+ T cells proliferation but is unable to drive cytokine production in the absence of TCR activation or IL-12/IL-4 stimulation in vitro. Eur J Immunol 32: 341–347

    Article  PubMed  CAS  Google Scholar 

  31. Alleva DG, Kaser SB, Monroy MA, Fenton MJ et al (1997) IL-15 functions as a potent autocrine regulator of macrophage proinflammatory cytokine production: Evidence for differential receptor subunit utilization associated with stimulation or inhibition. J Immunol 159: 2941–2951

    PubMed  CAS  Google Scholar 

  32. Neely GG, Robbins SM, Amankwah EK, Epelman S et al (2001) Lipopolysaccharidestimulated or granulocyte-macrophage colony-stimulating factor-stimulated monocytes rapidly express biologically active IL-15 on their cell surface independent of new protein synthesis. J Immunol 167: 5011–5017

    PubMed  CAS  Google Scholar 

  33. Mohamadzadeh M, Berard F, Essert G, Chalouni C et al (2001) Interleukin 15 skews monocyte differentiation into dendritic cells with features of Langerhans cells. J Exp Med 194: 1013–1020

    Article  PubMed  CAS  Google Scholar 

  34. Ohteki T, Suzue K, Maki C, Ota T et al (2001) Critical role of IL-15-IL-15R for antigenpresenting cell functions in the innate immune response. Nat Immunol 2: 1138–1143

    Article  PubMed  CAS  Google Scholar 

  35. Feau S, Facchinetti V, Granucci F, Citterio S et al (2005) Dendritic cell-derived IL-2 production is regulated by IL-15 in humans and in mice. Blood 105: 697–702

    Article  PubMed  CAS  Google Scholar 

  36. Girard D, Paquet ME, Paquin R, Beaulieu AD (1996) Differential effects of interleukin-15 (IL-15) and IL-2 on human neutrophils: Modulation of phagocytosis, cytoskeleton rearrangement, gene expression, and apoptosis by IL-15. Blood 88: 3176–3184

    PubMed  CAS  Google Scholar 

  37. Girard D, Boiani N, Beaulieu AD (1998) Human neutrophils express the interleukin-15 receptor alpha chain (IL-15Ralpha) but not the IL-9Ralpha component. Clin Immunol Immunopathol 88: 232–240

    Article  PubMed  CAS  Google Scholar 

  38. Bouchard A, Ratthe C, Girard D (2004) Interleukin-15 delays human neutrophils apoptosis by intracellular events and not via extracellular factors: Role of Mcl-1 and decreased activity of caspase-3 and caspase-8. J Leukoc Biol 75: 893–900

    Article  PubMed  CAS  Google Scholar 

  39. Hoontrakoon R, Chu WH, Gardai SJ, Wenzel SE et al (2002) Interleukin-15 inhibits spontaneous apoptosis in human eosinophils via autocrine production of granulocyte macrophage-colony stimulation factor and nuclear factor-kB activation. Am J Respir Cell Mol Biol 26: 404–12

    PubMed  CAS  Google Scholar 

  40. Tagaya Y, Bamford RN, DeFilippis AP, Waldmann TA (1996) IL-15: A pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels. Immunity. 4: 329–36

    Article  PubMed  CAS  Google Scholar 

  41. Masuda A, Matsuguchi T, Yamaki K, Hayakawa T, Yoshikai Y (2001) Interleukin-15 prevents mouse mast cell apoptosis through STAT6-mediated Bcl-xL expression. J Biol Chem 276: 26107–13

    Article  PubMed  CAS  Google Scholar 

  42. Ogata Y, Kukita A, Kukita T, Komine M et al (1999) A novel role of IL-15 in the development of osteoclasts: Inability to replace its activity with IL-2. J Immunol 162: 2754–2760

    PubMed  CAS  Google Scholar 

  43. Briard D, Brouty-Boye D, Azzarone B, Jasmin C (2002) Fibroblasts from human spleen regulate NK cell differentiation from blood CD34+ progenitors via cell surface IL-15. J Immunol 168: 4326–32

    PubMed  CAS  Google Scholar 

  44. Rappl G, Kapsokefalou A, Heuser C, Rossler M et al (2001) Dermal fibroblasts sustain proliferation of activated T cells via membrane-bound interleukin-15 upon long-term stimulation with tumor necrosis factor-α. J Invest Dermatol 116: 102–9

    Article  PubMed  CAS  Google Scholar 

  45. Kotake S, Schumacher HR Jr, Yarboro CH, Arayssi TK et al (1997) In vivo gene expression of type 1 and type 2 cytokines in synovial tissues from patients in early stages of rheumatoid, reactive, and undifferentiated arthritis. Proc Assoc Am Physicians 109: 286–301

    PubMed  CAS  Google Scholar 

  46. McInnes IB, Leung BP, Feng GJ, Sturrock RD et al (1998) A role for IL-15 in rheumatoid arthritis. Nat Med 4: 645

    Article  Google Scholar 

  47. Raza K, Falciani F, Curnow SJ, Ross EJ et al (2005) Early rheumatoid arthritis is char acterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther 7: R784–95

    Article  PubMed  CAS  Google Scholar 

  48. Aringer M, Stummvoll GH, Steiner G, Koller M et al (2001) Serum interleukin-15 is elevated in systemic lupus erythematosus. Rheumatology 40: 876–881

    Article  PubMed  CAS  Google Scholar 

  49. Klimiuk PA, Sierakowski S, Latosiewicz R, Cylwik B et al (2001) Serum cytokines in different histological variants of rheumatoid arthritis. J Rheumatol 28: 1211–1217

    PubMed  CAS  Google Scholar 

  50. McInnes IB, al-Mughales J, Field M, Leung BP et al (1996) The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis. Nat Med 2: 175–182

    Article  PubMed  CAS  Google Scholar 

  51. Thurkow EW, van der Heijden IM, Breedveld FC, Smeets TJ et al (1997) Increased expression of IL-15 in the synovium of patients with rheumatoid arthritis compared with patients with Yersinia-induced arthritis and osteoarthritis. J Pathol 181: 444–450

    Article  PubMed  CAS  Google Scholar 

  52. Oppenheimer-Marks N, Brezinschek RI, Mohamadzadeh M, Vita R et al (1998) Interleukin 15 is produced by endothelial cells and increases the transendothelial migration of T cells in vitro and in the SCID mouse-human rheumatoid arthritis model in vivo. J Clin Invest 101: 1261–1272

    Article  PubMed  CAS  Google Scholar 

  53. Scola MP, Thompson SD, Brunner HI, Tsoras MK et al (2002) Interferon-gamma: Interleukin 4 ratios and associated type 1 cytokine expression in juvenile rheumatoid arthritis synovial tissue. J Rheumatol 29: 369–378

    PubMed  CAS  Google Scholar 

  54. Rappl G, Kapsokefalou A, Heuser C, Rossler M et al (2001) Dermal fibroblasts sustain proliferation of activated T cells via membrane-bound interleukin-15 upon long-term stimulation with tumor necrosis factor-alpha. J Invest Dermatol 116: 102–109

    Article  PubMed  CAS  Google Scholar 

  55. Sen M, Lauterbach K, El-Gabalawy H, Firestein GS et al (2000) Expression and function of wingless and frizzled homologs in rheumatoid arthritis. Proc Natl Acad Sci USA 97: 2791–2796

    Article  PubMed  CAS  Google Scholar 

  56. Sen M, Chamorro M, Reifert J, Corr M et al (2001) Blockade of Wnt-5A/frizzled 5 signaling inhibits rheumatoid synoviocyte activation. Arthritis Rheum 44: 772–781

    Article  PubMed  CAS  Google Scholar 

  57. Ruchatz H, Leung BP, Wei XQ, McInnes IB et al (1998) Soluble IL-15 receptor alphachain administration prevents murine collagen-induced arthritis: A role for IL-15 in development of antigen-induced immunopathology. J Immunol 160: 5654–5660

    PubMed  CAS  Google Scholar 

  58. Wei X, Orchardson M, Gracie JA, Leung BP et al (2001) The Sushi domain of soluble IL-15 receptor alpha is essential for binding IL-15 and inhibiting inflammatory and allogenic responses in vitro and in vivo. J Immunol 167: 277–282

    CAS  Google Scholar 

  59. Kim YS, Maslinski W, Zheng XX, Stevens AC et al (1998) Targeting the IL-15 receptor with an antagonist IL-15 mutant/Fc gamma2a protein blocks delayed-type hypersensitivity. J Immunol 160: 5742–5748

    PubMed  CAS  Google Scholar 

  60. Ferrari-Lacraz S, Zheng XX, Kim YS, Li Y et al (2001) An antagonist IL-15/Fc protein prevents costimulation blockade-resistant rejection. J Immunol 167: 3478–3485

    PubMed  CAS  Google Scholar 

  61. Ferrari-Lacraz S, Zanelli E, Neuberg M, Donskoy E et al (2004) Targeting IL-15 receptor-bearing cells with an antagonist mutant IL-15/Fc protein prevents disease development and progression in murine collagen-induced arthritis. J Immunol 173: 5818–26

    PubMed  CAS  Google Scholar 

  62. Villadsen LS, Schuurman J, Beurskens F, Dam TN et al (2003) Resolution of psoriasis upon blockade of IL-15 biological activity in axenograft mouse model. J Clin Invest 112: 1571–80

    PubMed  CAS  Google Scholar 

  63. Baslund B, Tvede N, Danneskiold-Samsoe B, Larsson P et al (2005) Targeting interleukin-15 in patients with rheumatoid arthritis: A proof-of-concept study. Arthritis Rheum 52: 2686–92

    Article  PubMed  CAS  Google Scholar 

  64. Mcinnes IB, Martin R, Zimmermann-Gorska I, Nayiager S et al (2006) Safety and efficacy of a human monoclonal antibody to IL-15 (AMG 714) in patients with rheumatoid arthritis: Results of a multicenter, randomized, double-blind, placebo-controlled trial Ann Rheum Dis 65: EULAR Supplement

    Google Scholar 

  65. Kirman I, Nielsen OH (1996) Increased numbers of interleukin-15-expressing cells in active ulcerative colitis. Am J Gastroenterol 91: 1789–1794

    PubMed  CAS  Google Scholar 

  66. Kakumu S, Okumura A, Ishikawa T, Yano M et al (1997) Serum levels of IL-10, IL-15 and soluble tumour necrosis factor-alpha (TNF-alpha) receptors in type C chronic liver disease. Clin Exp Immunol 109: 458–463

    Article  PubMed  CAS  Google Scholar 

  67. Kivisakk P, Matusevicius D, He B, Soderstrom M et al (1998) IL-15 mRNA expression is up-regulated in blood and cerebrospinal fluid mononuclear cells in multiple sclerosis (MS). Clin Exp Immunol 111: 193–197

    Article  PubMed  CAS  Google Scholar 

  68. Stegall T, Krolick KA (2001) Myocytes respond in vivo to an antibody reactive with the acetylcholine receptor by upregulating interleukin-15: An interferon-gamma activator with the potential to influence the severity and course of experimental myasthenia gravis. J Neuroimmunol 119: 377–386

    Article  PubMed  CAS  Google Scholar 

  69. Agostini C, Trentin L, Facco M, Sancetta R et al (1996) Role of IL-15, IL-2, and their receptors in the development of T cell alveolitis in pulmonary sarcoidosis. J Immunol 157: 910–918

    PubMed  CAS  Google Scholar 

  70. Muro S, Taha R, Tsicopoulos A, Olivenstein R et al (2001) Expression of IL-15 in inflammatory pulmonary diseases. J Allergy Clin Immunol 108: 970–975

    Article  PubMed  CAS  Google Scholar 

  71. Morris JC, Janik JE, White JD, Fleisher TA et al (2006) Preclinical and phase I clinical trial of blockade of IL-15 using Mikbeta1 monoclonal antibody in T cell large granular lymphocyte leukemia. Proc Natl Acad Sci USA 103: 401–6

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre for Rheumatic Diseases, Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, UK

    Jagtar Nijar Singh & Iain B. McInnes

Authors
  1. Jagtar Nijar Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Iain B. McInnes
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Clinical Immunology and Rheumatology EULAR & FOCIS Center of Excellence Academic Medical Center, University of Amsterdam, Meibergdreef 9, Room F4-218, 1105, AZ Amsterdam, The Netherlands

    Paul-Peter Tak

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Birkhäuser Verlag Basel/Switzerland

About this chapter

Cite this chapter

Singh, J.N., McInnes, I.B. (2009). Interleukin-15. In: Tak, PP. (eds) New Therapeutic Targets in Rheumatoid Arthritis. Progress in Inflammation Research. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-8238-4_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-7643-8238-4_5

  • Publisher Name: Birkhäuser Basel

  • Print ISBN: 978-3-7643-8237-7

  • Online ISBN: 978-3-7643-8238-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation