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Interleukin-15

  • Jagtar Nijar Singh
  • Iain B. McInnes
Part of the Progress in Inflammation Research book series (PIR)

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.

Keywords

Rheumatoid Arthritis Psoriatic Arthritis Reactive Arthritis Rheumatoid Arthritis Synovial Fluid Large Granular Lymphocyte 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 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: 965–968PubMedCrossRefGoogle Scholar
  2. 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: 4940–4944PubMedCrossRefGoogle Scholar
  3. 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: 19–49PubMedCrossRefGoogle Scholar
  4. 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: 259–280PubMedCrossRefGoogle Scholar
  5. 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: 4418–4426PubMedGoogle Scholar
  6. 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: 14444–14449PubMedCrossRefGoogle Scholar
  7. 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: 936–942PubMedGoogle Scholar
  8. 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: 1265–1274PubMedCrossRefGoogle Scholar
  9. 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: 19–28PubMedCrossRefGoogle Scholar
  10. 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: 26978–84PubMedCrossRefGoogle Scholar
  11. 11.
    Waldmann T, Tagaya Y, Bamford R (1998) Interleukin-2, interleukin-15, and their receptors. Int Rev Immunol 16: 205–226PubMedCrossRefGoogle Scholar
  12. 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: 329–336PubMedCrossRefGoogle Scholar
  13. 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: 26978–26984PubMedCrossRefGoogle Scholar
  14. 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: 4260–70PubMedCrossRefGoogle Scholar
  15. 15.
    Dubois S, Mariner J, Waldmann TA, Tagaya Y (2002) IL-15Ra recycles and presents IL-15 in trans to neighboring cells. Immunity 17: 537–47PubMedCrossRefGoogle Scholar
  16. 16.
    Budagian V, Bulanova E, Orinska Z, Pohl T et al (2004) Reverse signaling through membrane-bound interleukin-15. J Biol Chem 279: 42192–201PubMedCrossRefGoogle Scholar
  17. 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: 4225–34PubMedGoogle Scholar
  18. 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: 663–669PubMedGoogle Scholar
  19. 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: 4513–4521PubMedGoogle Scholar
  20. 20.
    Kanegane H, Tosato G (1996) Activation of naive and memory T cells by interleukin-15. Blood 88: 230–235PubMedGoogle Scholar
  21. 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: 238–244PubMedCrossRefGoogle Scholar
  22. 22.
    Wilkinson PC, Liew FY (1995) Chemoattraction of human blood T lymphocytes by interleukin-15. J Exp Med 181: 1255–1259PubMedCrossRefGoogle Scholar
  23. 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: 230–236PubMedCrossRefGoogle Scholar
  24. 24.
    Nieto M, del Pozo MA, Sanchez-Madrid F (1996) Interleukin-15 induces adhesion receptor redistribution in T lymphocytes. Eur J Immunol 26: 1302–1307PubMedCrossRefGoogle Scholar
  25. 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: 1067–1077PubMedCrossRefGoogle Scholar
  26. 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: 2400–2405PubMedGoogle Scholar
  27. 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: 6007–6011PubMedGoogle Scholar
  28. 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: 1198–1203PubMedGoogle Scholar
  29. 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: 1711–1720PubMedCrossRefGoogle Scholar
  30. 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: 341–347PubMedCrossRefGoogle Scholar
  31. 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: 2941–2951PubMedGoogle Scholar
  32. 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: 5011–5017PubMedGoogle Scholar
  33. 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: 1013–1020PubMedCrossRefGoogle Scholar
  34. 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: 1138–1143PubMedCrossRefGoogle Scholar
  35. 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: 697–702PubMedCrossRefGoogle Scholar
  36. 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: 3176–3184PubMedGoogle Scholar
  37. 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: 232–240PubMedCrossRefGoogle Scholar
  38. 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: 893–900PubMedCrossRefGoogle Scholar
  39. 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: 404–12PubMedGoogle Scholar
  40. 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: 329–36PubMedCrossRefGoogle Scholar
  41. 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: 26107–13PubMedCrossRefGoogle Scholar
  42. 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: 2754–2760PubMedGoogle Scholar
  43. 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: 4326–32PubMedGoogle Scholar
  44. 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: 102–9PubMedCrossRefGoogle Scholar
  45. 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: 286–301PubMedGoogle Scholar
  46. 46.
    McInnes IB, Leung BP, Feng GJ, Sturrock RD et al (1998) A role for IL-15 in rheumatoid arthritis. Nat Med 4: 645CrossRefGoogle Scholar
  47. 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: R784–95PubMedCrossRefGoogle Scholar
  48. 48.
    Aringer M, Stummvoll GH, Steiner G, Koller M et al (2001) Serum interleukin-15 is elevated in systemic lupus erythematosus. Rheumatology 40: 876–881PubMedCrossRefGoogle Scholar
  49. 49.
    Klimiuk PA, Sierakowski S, Latosiewicz R, Cylwik B et al (2001) Serum cytokines in different histological variants of rheumatoid arthritis. J Rheumatol 28: 1211–1217PubMedGoogle Scholar
  50. 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: 175–182PubMedCrossRefGoogle Scholar
  51. 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: 444–450PubMedCrossRefGoogle Scholar
  52. 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: 1261–1272PubMedCrossRefGoogle Scholar
  53. 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: 369–378PubMedGoogle Scholar
  54. 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: 102–109PubMedCrossRefGoogle Scholar
  55. 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: 2791–2796PubMedCrossRefGoogle Scholar
  56. 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: 772–781PubMedCrossRefGoogle Scholar
  57. 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: 5654–5660PubMedGoogle Scholar
  58. 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: 277–282Google Scholar
  59. 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: 5742–5748PubMedGoogle Scholar
  60. 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: 3478–3485PubMedGoogle Scholar
  61. 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: 5818–26PubMedGoogle Scholar
  62. 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: 1571–80PubMedGoogle Scholar
  63. 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: 2686–92PubMedCrossRefGoogle Scholar
  64. 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 SupplementGoogle Scholar
  65. 65.
    Kirman I, Nielsen OH (1996) Increased numbers of interleukin-15-expressing cells in active ulcerative colitis. Am J Gastroenterol 91: 1789–1794PubMedGoogle Scholar
  66. 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: 458–463PubMedCrossRefGoogle Scholar
  67. 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: 193–197PubMedCrossRefGoogle Scholar
  68. 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: 377–386PubMedCrossRefGoogle Scholar
  69. 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: 910–918PubMedGoogle Scholar
  70. 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: 970–975PubMedCrossRefGoogle Scholar
  71. 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: 401–6PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2009

Authors and Affiliations

  • Jagtar Nijar Singh
    • 1
  • Iain B. McInnes
    • 1
  1. 1.Centre for Rheumatic Diseases, Division of Immunology, Infection and InflammationUniversity of GlasgowGlasgowUK

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