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:

The IL-1 family: regulators of immunity

Nature Reviews Immunology volume 10, pages 89–102 (2010)Cite this article

Subjects

Key Points

  • The interleukin-1 (IL-1) cytokine family comprises 11 members: IL-1α, IL-1β, IL-1 receptor antagonist (IL-1Ra), IL-18, IL-33 and IL-1F5–IL-1F10. The biology of IL-1F5–IL-1F10 is less well characterized than that of IL-1, IL-18 and IL-33.

  • IL-1 family members promote the activity of cells of the innate immune system, such as neutrophils, eosinophils, basophils, mast cells and natural killer cells.

  • IL-1 family members also have important functions in activating and reinforcing the function of polarized T cells. As a general rule, IL-18 mainly affects T helper 1 (TH1) cells, IL-33 mainly affects TH2 cells and IL-1 has a key role in TH17 cell differentiation and maintenance, but there are exceptions.

  • IL-1 family members have roles in mouse models of immune-mediated diseases such as arthritis, asthma, inflammatory bowel disease, multiple sclerosis and psoriasis. Although they are thought to influence these diseases in humans, this has not been tested except for the case of IL-1 in rheumatoid arthritis.

  • Diseases driven by innate immune cells, such as atherosclerosis and the response to tissue injury also seem to have a large contribution from IL-1 family members. This has been shown clinically in the case of autoinflammatory syndromes.

Abstract

Over recent years it has become increasingly clear that innate immune responses can shape the adaptive immune response. Among the most potent molecules of the innate immune system are the interleukin-1 (IL-1) family members. These evolutionarily ancient cytokines are made by and act on innate immune cells to influence their survival and function. In addition, they act directly on lymphocytes to reinforce certain adaptive immune responses. This Review provides an overview of both the long-established and more recently characterized members of the IL-1 family. In addition to their effects on immune cells, their involvement in human disease and disease models is discussed.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Interleukin-1 family members, processing, receptors and regulation.
Figure 2: Cellular sources of interleukin-1 family members and their effects on innate immune cells.
Figure 3: The effects of interleukin-1 family members on CD4+ T cells.

Similar content being viewed by others

References

  1. Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Dinarello, C. A. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol. 27, 519–550 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. O'Neill, L. A. The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress. Immunol. Rev. 226, 10–18 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Smith, D. E. IL-33: a tissue derived cytokine pathway involved in allergic inflammation and asthma. Clin. Exp. Allergy 3 Nov 2009 (doi:10.1111/j.1365-2009.03384.x).

  5. Gabay, C. & McInnes, I. B. The biological and clinical importance of the 'new generation' cytokines in rheumatic diseases. Arthritis Res. Ther. 11, 230 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sims, J. E. et al. A new nomenclature for IL-1-family genes. Trends Immunol. 22, 536–537 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Taylor, S. L., Renshaw, B. R., Garka, K. E., Smith, D. E. & Sims, J. E. Genomic organization of the interleukin-1 locus. Genomics 79, 726–733 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Nicklin, M. J. et al. A sequence-based map of the nine genes of the human interleukin-1 cluster. Genomics 79, 718–725 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229–265 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Luthi, A. U. et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 31, 84–98 (2009). This report shows that caspase 1 is not involved in processing of IL-33, but instead that pro-apoptotic caspases cleave and inactivate it.

    Article  CAS  PubMed  Google Scholar 

  11. Talabot-Ayer, D., Lamacchia, C., Gabay, C. & Palmer, G. Interleukin-33 is biologically active independently of caspase-1 cleavage. J. Biol. Chem. 284, 19420–19426 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dinarello, C. A. Biologic basis for interleukin-1 in disease. Blood 87, 2095–2147 (1996).

    CAS  PubMed  Google Scholar 

  13. Kurt-Jones, E. A., Beller, D. I., Mizel, S. B. & Unanue, E. R. Identification of a membrane-associated interleukin 1 in macrophages. Proc. Natl Acad. Sci. USA 82, 1204–1208 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rausch, U. P. et al. Transcriptional and translational regulation of IL-1α and IL-1β account for the control of IL-1 in experimental yersiniosis. Cytokine 6, 504–511 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. Horai, R. et al. Production of mice deficient in genes for interleukin (IL)-1α, IL-1β, IL-1α/β, and IL-1 receptor antagonist shows that IL-1β is crucial in turpentine-induced fever development and glucocorticoid secretion. J. Exp. Med. 187, 1463–1475 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nakae, S. et al. IL-1α, but not IL-1β, is required for contact-allergen-specific T cell activation during the sensitization phase in contact hypersensitivity. Int. Immunol. 13, 1471–1478 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Nakae, S. et al. IL-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response. Int. Immunol. 15, 483–490 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Buryskova, M., Pospisek, M., Grothey, A., Simmet, T. & Burysek, L. Intracellular interleukin-1α functionally interacts with histone acetyltransferase complexes. J. Biol. Chem. 279, 4017–4026 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Werman, A. et al. The precursor form of IL-1α is an intracrine proinflammatory activator of transcription. Proc. Natl Acad. Sci. USA 101, 2434–2439 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Greenfeder, S. A. et al. Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex. J. Biol. Chem. 270, 13757–13765 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Arend, W. P., Malyak, M., Guthridge, C. J. & Gabay, C. Interleukin-1 receptor antagonist: role in biology. Annu. Rev. Immunol. 16, 27–55 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Palmer, G., Talabot-Ayer, D., Kaya, G. & Gabay, C. Type I IL-1 receptor mediates IL-1 and intracellular IL-1 receptor antagonist effects in skin inflammation. J. Invest. Dermatol. 127, 1938–1946 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Colotta, F. et al. Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science 261, 472–475 (1993).

    Article  CAS  PubMed  Google Scholar 

  24. Smith, D. E. et al. The soluble form of IL-1 receptor accessory protein enhances the ability of soluble type II IL-1 receptor to inhibit IL-1 action. Immunity 18, 87–96 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Gu, Y. et al. Activation of interferon-γ inducing factor mediated by interleukin-1β converting enzyme. Science 275, 206–209 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Liang, D., Ma, W., Yao, C., Liu, H. & Chen, X. Imbalance of interleukin 18 and interleukin 18 binding protein in patients with lupus nephritis. Cell. Mol. Immunol. 3, 303–306 (2006).

    CAS  PubMed  Google Scholar 

  27. Schmitz, J. et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23, 479–490 (2005). The identification of IL-33 finally provided a ligand for the previously orphan T H 2 cell-associated receptor ST2, and clarified its biology.

    Article  CAS  PubMed  Google Scholar 

  28. Baekkevold, E. S. et al. Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules. Am. J. Pathol. 163, 69–79 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Roussel, L., Erard, M., Cayrol, C. & Girard, J. P. Molecular mimicry between IL-33 and KSHV for attachment to chromatin through the H2A–H2B acidic pocket. EMBO Rep. 9, 1006–1012 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cayrol, C. & Girard, J. P. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc. Natl Acad. Sci. USA 106, 9021–9026 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hayakawa, M. et al. Mature interleukin-33 is produced by calpain-mediated cleavage in vivo. Biochem. Biophys. Res. Commun. 387, 218–222 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Palmer, G. et al. The IL-1 receptor accessory protein (AcP) is required for IL-33 signalling and soluble AcP enhances the ability of soluble ST2 to inhibit IL-33. Cytokine 42, 358–364 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Towne, J. E., Garka, K. E., Renshaw, B. R., Virca, G. D. & Sims, J. E. Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-κB and MAPKs. J. Biol. Chem. 279, 13677–13688 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Dunn, E., Sims, J. E., Nicklin, M. J. & O'Neill, L. A. Annotating genes with potential roles in the immune system: six new members of the IL-1 family. Trends Immunol. 22, 533–536 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Debets, R. et al. Two novel IL-1 family members, IL-1δ and IL-1ɛ, function as an antagonist and agonist of NF-κB activation through the orphan IL-1 receptor-related protein 2. J. Immunol. 167, 1440–1446 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Dunn, E. F. et al. High-resolution structure of murine interleukin 1 homologue IL-1F5 reveals unique loop conformations for receptor binding specificity. Biochemistry 42, 10938–10944 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Kumar, S. et al. Interleukin-1F7B (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-γ production. Cytokine 18, 61–71 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Pan, G. et al. IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp. Cytokine 13, 1–7 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Bufler, P. et al. A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity. Proc. Natl Acad. Sci. USA 99, 13723–13728 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sharma, S. et al. The IL-1 family member 7b translocates to the nucleus and downregulates proinflammatory cytokines. J. Immunol. 180, 5477–5482 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Grimsby, S. et al. Proteomics-based identification of proteins interacting with Smad3: SREBP-2 forms a complex with Smad3 and inhibits its transcriptional activity. FEBS Lett. 577, 93–100 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Lin, H. et al. Cloning and characterization of IL-1HY2, a novel interleukin-1 family member. J. Biol. Chem. 276, 20597–20602 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Polentarutti, N. et al. Unique pattern of expression and inhibition of IL-1 signalling by the IL-1 receptor family member TIR8/SIGIRR. Eur. Cytokine Netw. 14, 211–218 (2003).

    CAS  PubMed  Google Scholar 

  44. Wald, D. et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signalling. Nature Immunol. 4, 920–927 (2003).

    Article  CAS  Google Scholar 

  45. Bozza, S. et al. Lack of Toll IL-1R8 exacerbates Th17 cell responses in fungal infection. J. Immunol. 180, 4022–4031 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Garlanda, C., Anders, H. J. & Mantovani, A. TIR8/SIGIRR: an IL-1R/TLR family member with regulatory functions in inflammation and T cell polarization. Trends Immunol. 30, 439–446 (2009). An excellent summary of the biology of SIGIRR (originally identified by this group as TIR8).

    Article  CAS  PubMed  Google Scholar 

  47. Suzukawa, M. et al. Interleukin-33 enhances adhesion, CD11b expression and survival in human eosinophils. Lab. Invest. 88, 1245–1253 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Gudbjartsson, D. F. et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nature Genet. 41, 342–347 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Townsend, M. J., Fallon, P. G., Matthews, D. J., Jolin, H. E. & McKenzie, A. N. T1/ST2-deficient mice demonstrate the importance of T1/ST2 in developing primary T helper cell type 2 responses. J. Exp. Med. 191, 1069–1076 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Senn, K. A. et al. T1-deficient and T1-Fc-transgenic mice develop a normal protective Th2-type immune response following infection with Nippostrongylus brasiliensis. Eur. J. Immunol. 30, 1929–1938 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Kondo, Y. et al. Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int. Immunol. 20, 791–800 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Allakhverdi, Z., Smith, D. E., Comeau, M. R. & Delespesse, G. Cutting edge: the ST2 ligand IL-33 potently activates and drives maturation of human mast cells. J. Immunol. 179, 2051–2054 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Pushparaj, P. N. et al. The cytokine interleukin-33 mediates anaphylactic shock. Proc. Natl Acad. Sci. USA 106, 9773–9778 (2009). This paper shows a new link between IL-33, mast cells and allergen-independent anaphylaxis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wynn, T. A. Basophils trump dendritic cells as APCs for TH2 responses. Nature Immunol. 10, 679–681 (2009).

    Article  CAS  Google Scholar 

  55. Yoshimoto, T. & Nakanishi, K. Roles of IL-18 in basophils and mast cells. Allergol. Int. 55, 105–113 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Schneider, E. et al. IL-33 activates unprimed murine basophils directly in vitro and induces their in vivo expansion indirectly by promoting haematopoietic growth factor production. J. Immunol. 15, 3591–3597 (2009).

    Article  Google Scholar 

  57. Massey, W. A. et al. Recombinant human IL-1α and -1β potentiate IgE-mediated histamine release from human basophils. J. Immunol. 143, 1875–1880 (1989).

    CAS  PubMed  Google Scholar 

  58. Yoshimoto, T. et al. IL-18, although antiallergic when administered with IL-12, stimulates IL-4 and histamine release by basophils. Proc. Natl Acad. Sci. USA 96, 13962–13966 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Suzukawa, M. et al. An IL-1 cytokine member, IL-33, induces human basophil activation via its ST2 receptor. J. Immunol. 181, 5981–5989 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Chaix, J. et al. Cutting edge: priming of NK cells by IL-18. J. Immunol. 181, 1627–1631 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Hyodo, Y. et al. IL-18 upregulates perforin-mediated NK activity without increasing perforin messenger RNA expression by binding to constitutively expressed IL-18 receptor. J. Immunol. 162, 1662–1668 (1999).

    CAS  PubMed  Google Scholar 

  62. Hashimoto, W. et al. Differential antitumour effects of administration of recombinant IL-18 or recombinant IL-12 are mediated primarily by Fas–Fas ligand- and perforin-induced tumour apoptosis, respectively. J. Immunol. 163, 583–589 (1999).

    CAS  PubMed  Google Scholar 

  63. Smithgall, M. D. et al. IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells. Int. Immunol. 20, 1019–1030 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Bourgeois, E. et al. The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-γ production. Eur. J. Immunol. 39, 1046–1055 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Uchida, T. et al. IL-18 time-dependently modulates Th1/Th2 cytokine production by ligand-activated NKT cells. Eur. J. Immunol. 37, 966–977 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Chung, Y. et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30, 576–587 (2009). This paper currently provides the broadest study of the involvement of IL-1 in T H 17 cell development.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kryczek, I. et al. Cutting edge: opposite effects of IL-1 and IL-2 on the regulation of IL-17+ T cell pool IL-1 subverts IL-2-mediated suppression. J. Immunol. 179, 1423–1426 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Ben-Sasson, S. Z. et al. IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc. Natl Acad. Sci. USA 106, 7119–7124 (2009). This study shows the effects of IL-1 on T cell responses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. O'Sullivan, B. J. et al. IL-1β breaks tolerance through expansion of CD25+ effector T cells. J. Immunol. 176, 7278–7287 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Hata, H., Yoshimoto, T., Hayashi, N., Hada, T. & Nakanishi, K. IL-18 together with anti-CD3 antibody induces human Th1 cells to produce Th1- and Th2-cytokines and IL-8. Int. Immunol. 16, 1733–1739 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Guo, L. et al. IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc. Natl Acad. Sci. USA 106, 13463–13468 (2009). An excellent analysis of the effects of IL-1, IL-18 and IL-33 on different T H cell lineages.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lichtman, A. H., Chin, J., Schmidt, J. A. & Abbas, A. K. Role of interleukin 1 in the activation of T lymphocytes. Proc. Natl Acad. Sci. USA 85, 9699–9703 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Acosta-Rodriguez, E. V., Napolitani, G., Lanzavecchia, A. & Sallusto, F. Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T helper cells. Nature Immunol. 8, 942–949 (2007).

    Article  CAS  Google Scholar 

  74. Wilson, N. J. et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nature Immunol. 8, 950–957 (2007).

    Article  CAS  Google Scholar 

  75. Sutton, C., Brereton, C., Keogh, B., Mills, K. H. & Lavelle, E. C. A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J. Exp. Med. 203, 1685–1691 (2006). The first description of the involvement of IL-1 in T H 17 cell development in the context of EAE.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Staschke, K. A. et al. IRAK4 kinase activity is required for Th17 differentiation and Th17-mediated disease. J. Immunol. 183, 568–577 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Atarashi, K. et al. ATP drives lamina propria TH17 cell differentiation. Nature 455, 808–812 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Meng, G., Zhang, F., Fuss, I., Kitani, A. & Strober, W. A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses. Immunity 30, 860–874 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shen, X., Tian, Z., Holtzman, M. J. & Gao, B. Cross-talk between interleukin 1β (IL-1β) and IL-6 signalling pathways: IL-1β selectively inhibits IL-6-activated signal transducer and activator of transcription factor 1 (STAT1) by a proteasome-dependent mechanism. Biochem. J. 352, 913–919 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Brustle, A. et al. The development of inflammatory TH-17 cells requires interferon-regulatory factor 4. Nature Immunol. 8, 958–966 (2007).

    Article  CAS  Google Scholar 

  81. Laurence, A. et al. Interleukin-2 signalling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Maitra, U., Davis, S., Reilly, C. M. & Li, L. Differential regulation of Foxp3 and IL-17 expression in CD4 T helper cells by IRAK-1. J. Immunol. 182, 5763–5769 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Wang, D., Fasciano, S. & Li, L. The interleukin-1 receptor associated kinase 1 contributes to the regulation of NFAT. Mol. Immunol. 45, 3902–3908 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sutton, C. E. et al. Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity. Immunity 31, 331–341 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Carroll, R. G. et al. Distinct effects of IL-18 on the engraftment and function of human effector CD8 T cells and regulatory T cells. PLoS One 3, e3289 (2008). This study showed that T Reg cells express IL-18R and are inhibited in vivo by IL-18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Maliszewski, C. R. et al. Cytokine receptors and B cell functions. I. Recombinant soluble receptors specifically inhibit IL-1- and IL-4-induced B cell activities in vitro. J. Immunol. 144, 3028–3033 (1990).

    CAS  PubMed  Google Scholar 

  88. Rousset, F., Garcia, E. & Banchereau, J. Cytokine-induced proliferation and immunoglobulin production of human B lymphocytes triggered through their CD40 antigen. J. Exp. Med. 173, 705–710 (1991).

    Article  CAS  PubMed  Google Scholar 

  89. Ohshima, Y. et al. Expression and function of OX40 ligand on human dendritic cells. J. Immunol. 159, 3838–3848 (1997).

    CAS  PubMed  Google Scholar 

  90. Nakae, S., Asano, M., Horai, R., Sakaguchi, N. & Iwakura, Y. IL-1 enhances T cell-dependent antibody production through induction of CD40 ligand and OX40 on T cells. J. Immunol. 167, 90–97 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Schmitz, N., Kurrer, M. & Kopf, M. The IL-1 receptor 1 is critical for Th2 cell type airway immune responses in a mild but not in a more severe asthma model. Eur. J. Immunol. 33, 991–1000 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Yoshimoto, T., Okamura, H., Tagawa, Y. I., Iwakura, Y. & Nakanishi, K. Interleukin 18 together with interleukin 12 inhibits IgE production by induction of interferon-γ production from activated B cells. Proc. Natl Acad. Sci. USA 94, 3948–3953 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Nakae, S. et al. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc. Natl Acad. Sci. USA 100, 5986–5990 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Joosten, L. A. et al. IL-1αβ blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-α blockade only ameliorates joint inflammation. J. Immunol. 163, 5049–5055 (1999).

    CAS  PubMed  Google Scholar 

  95. Mertens, M. & Singh, J. A. Anakinra for rheumatoid arthritis: a systematic review. J. Rheumatol. 36, 1118–1125 (2009).

    Article  CAS  PubMed  Google Scholar 

  96. Verbsky, J. W. & White, A. J. Effective use of the recombinant interleukin 1 receptor antagonist anakinra in therapy resistant systemic onset juvenile rheumatoid arthritis. J. Rheumatol. 31, 2071–2075 (2004).

    PubMed  Google Scholar 

  97. Pascual, V., Allantaz, F., Arce, E., Punaro, M. & Banchereau, J. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J. Exp. Med. 201, 1479–1486 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Gattorno, M. et al. The pattern of response to anti-interleukin-1 treatment distinguishes two subsets of patients with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 58, 1505–1515 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. So, A., De Smedt, T., Revaz, S. & Tschopp, J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res. Ther. 9, R28 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Palmer, G. et al. Inhibition of interleukin-33 signalling attenuates the severity of experimental arthritis. Arthritis Rheum. 60, 738–749 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. Xu, D. et al. IL-33 exacerbates antigen-induced arthritis by activating mast cells. Proc. Natl Acad. Sci. USA 105, 10913–10918 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Aliahmadi, E. et al. TLR2-activated human langerhans cells promote Th17 polarization via IL-1β, TGF-β and IL-23. Eur. J. Immunol. 39, 1221–1230 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Enk, A. H. & Katz, S. I. Early molecular events in the induction phase of contact sensitivity. Proc. Natl Acad. Sci. USA 89, 1398–1402 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Matsue, H., Cruz, P. D. Jr, Bergstresser, P. R. & Takashima, A. Langerhans cells are the major source of mRNA for IL-1β and MIP-1α among unstimulated mouse epidermal cells. J. Invest. Dermatol. 99, 537–541 (1992).

    Article  CAS  PubMed  Google Scholar 

  106. Schreiber, S. et al. Cytokine pattern of Langerhans cells isolated from murine epidermal cell cultures. J. Immunol. 149, 3524–3534 (1992).

    CAS  PubMed  Google Scholar 

  107. Cumberbatch, M., Dearman, R. J., Antonopoulos, C., Groves, R. W. & Kimber, I. Interleukin (IL)-18 induces Langerhans cell migration by a tumour necrosis factor-α- and IL-1β-dependent mechanism. Immunology 102, 323–330 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wang, B. et al. Contribution of Langerhans cell-derived IL-18 to contact hypersensitivity. J. Immunol. 168, 3303–3308 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Furue, M., Chang, C. H. & Tamaki, K. Interleukin-1 but not tumour necrosis factorα synergistically upregulates the granulocyte-macrophage colony-stimulating factor-induced B7-1 expression of murine Langerhans cells. Br. J. Dermatol. 135, 194–198 (1996).

    Article  CAS  PubMed  Google Scholar 

  110. Ozawa, H., Nakagawa, S., Tagami, H. & Aiba, S. Interleukin-1β and granulocyte-macrophage colony-stimulating factor mediate Langerhans cell maturation differently. J. Invest. Dermatol. 106, 441–445 (1996).

    Article  CAS  PubMed  Google Scholar 

  111. Jakob, T. & Udey, M. C. Regulation of E-cadherin-mediated adhesion in Langerhans cell-like dendritic cells by inflammatory mediators that mobilize Langerhans cells in vivo. J. Immunol. 160, 4067–4073 (1998).

    CAS  PubMed  Google Scholar 

  112. Shornick, L. P. et al. Mice deficient in IL-1β manifest impaired contact hypersensitivity to trinitrochlorobenzone. J. Exp. Med. 183, 1427–1436 (1996).

    Article  CAS  PubMed  Google Scholar 

  113. Plitz, T. et al. IL-18 binding protein protects against contact hypersensitivity. J. Immunol. 171, 1164–1171 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Enk, A. H., Angeloni, V. L., Udey, M. C. & Katz, S. I. An essential role for Langerhans cell-derived IL-1β in the initiation of primary immune responses in skin. J. Immunol. 150, 3698–3704 (1993).

    CAS  PubMed  Google Scholar 

  115. Watanabe, H. et al. Activation of the IL-1β-processing inflammasome is involved in contact hypersensitivity. J. Invest. Dermatol. 127, 1956–1963 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Lowes, M. A., Bowcock, A. M. & Krueger, J. G. Pathogenesis and therapy of psoriasis. Nature 445, 866–873 (2007).

    Article  CAS  PubMed  Google Scholar 

  117. Naik, S. M. et al. Human keratinocytes constitutively express interleukin-18 and secrete biologically active interleukin-18 after treatment with pro-inflammatory mediators and dinitrochlorobenzene. J. Invest. Dermatol. 113, 766–772 (1999).

    Article  CAS  PubMed  Google Scholar 

  118. Zhou, X. et al. Novel mechanisms of T-cell and dendritic cell activation revealed by profiling of psoriasis on the 63,100-element oligonucleotide array. Physiol. Genomics 13, 69–78 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Blumberg, H. et al. Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation. J. Exp. Med. 204, 2603–2614 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Piskin, G., Tursen, U., Sylva-Steenland, R. M., Bos, J. D. & Teunissen, M. B. Clinical improvement in chronic plaque-type psoriasis lesions after narrow-band UVB therapy is accompanied by a decrease in the expression of IFN-γ inducers — IL-12, IL-18 and IL-23. Exp. Dermatol. 13, 764–772 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Gottlieb, A. B. et al. TNF inhibition rapidly downregulates multiple proinflammatory pathways in psoriasis plaques. J. Immunol. 175, 2721–2729 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Shimizu, M. et al. Functional SNPs in the distal promoter of the ST2 gene are associated with atopic dermatitis. Hum. Mol. Genet. 14, 2919–2927 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Terada, M. et al. Contribution of IL-18 to atopic-dermatitis-like skin inflammation induced by Staphylococcus aureus product in mice. Proc. Natl Acad. Sci. USA 103, 8816–8821 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kawase, Y. et al. Exacerbated and prolonged allergic and non-allergic inflammatory cutaneous reaction in mice with targeted interleukin-18 expression in the skin. J. Invest. Dermatol. 121, 502–509 (2003).

    Article  CAS  PubMed  Google Scholar 

  125. Konishi, H. et al. IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions. Proc. Natl Acad. Sci. USA 99, 11340–11345 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Matsuki, T., Nakae, S., Sudo, K., Horai, R. & Iwakura, Y. Abnormal T cell activation caused by the imbalance of the IL-1/IL-1R antagonist system is responsible for the development of experimental autoimmune encephalomyelitis. Int. Immunol. 18, 399–407 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. McCandless, E. E. et al. IL-1R signaling within the central nervous system regulates CXCL12 expression at the blood-brain barrier and disease severity during experimental autoimmune encephalomyelitis. J. Immunol. 183, 613–620 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Nicoletti, F. et al. Circulating serum levels of IL-1ra in patients with relapsing remitting multiple sclerosis are normal during remission phases but significantly increased either during exacerbations or in response to IFN-β treatment. Cytokine 8, 395–400 (1996).

    Article  CAS  PubMed  Google Scholar 

  129. Burger, D. et al. Glatiramer acetate increases IL-1 receptor antagonist but decreases T cell-induced IL-1β in human monocytes and multiple sclerosis. Proc. Natl Acad. Sci. USA 106, 4355–4359 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Shi, F. D., Takeda, K., Akira, S., Sarvetnick, N. & Ljunggren, H. G. IL-18 directs autoreactive T cells and promotes autodestruction in the central nervous system via induction of IFN-γ by NK cells. J. Immunol. 165, 3099–3104 (2000).

    Article  CAS  PubMed  Google Scholar 

  131. Gutcher, I., Urich, E., Wolter, K., Prinz, M. & Becher, B. Interleukin 18-independent engagement of interleukin 18 receptor-α is required for autoimmune inflammation. Nature Immunol. 7, 946–953 (2006).

    Article  CAS  Google Scholar 

  132. Favilli, F. et al. IL-18 activity in systemic lupus erythematosus. Ann. NY Acad. Sci. 1173, 301–309 (2009).

    Article  CAS  PubMed  Google Scholar 

  133. Novick, D. et al. High circulating levels of free interleukin-18 in patients with active SLE in the presence of elevated levels of interleukin-18 binding protein. J. Autoimmun. 22 Aug 2009 (doi:10.1016/j.jaut.2009.08.002).

    Article  CAS  PubMed  Google Scholar 

  134. Wang, C. C. et al. Adenovirus expressing interleukin-1 receptor antagonist alleviates allergic airway inflammation in a murine model of asthma. Gene Ther. 13, 1414–1421 (2006).

    Article  CAS  PubMed  Google Scholar 

  135. Tanaka, H. et al. IL-18 might reflect disease activity in mild and moderate asthma exacerbation. J. Allergy Clin. Immunol. 107, 331–336 (2001).

    Article  CAS  PubMed  Google Scholar 

  136. Sugimoto, T. et al. Interleukin 18 acts on memory T helper cells type 1 to induce airway inflammation and hyperresponsiveness in a naive host mouse. J. Exp. Med. 199, 535–545 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Yamagata, S. et al. Interleukin-18-deficient mice exhibit diminished chronic inflammation and airway remodelling in ovalbumin-induced asthma model. Clin. Exp. Immunol. 154, 295–304 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Oshikawa, K. et al. Elevated soluble ST2 protein levels in sera of patients with asthma with an acute exacerbation. Am. J. Respir. Crit. Care Med. 164, 277–281 (2001).

    Article  CAS  PubMed  Google Scholar 

  139. Walzl, G. et al. Inhibition of T1/ST2 during respiratory syncytial virus infection prevents T helper cell type 2 (Th2)- but not Th1-driven immunopathology. J. Exp. Med. 193, 785–792 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Kearley, J., Buckland, K. F., Mathie, S. A. & Lloyd, C. M. Resolution of allergic inflammation and airway hyperreactivity is dependent upon disruption of the T1/ST2–IL-33 pathway. Am. J. Respir. Crit. Care Med. 179, 772–781 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Casini-Raggi, V. et al. Mucosal imbalance of IL-1 and IL-1 receptor antagonist in inflammatory bowel disease. A novel mechanism of chronic intestinal inflammation. J. Immunol. 154, 2434–2440 (1995).

    CAS  PubMed  Google Scholar 

  142. Netea, M. G. et al. NOD2 3020insC mutation and the pathogenesis of Crohn's disease: impaired IL-1β production points to a loss-of-function phenotype. Neth. J. Med. 63, 305–308 (2005).

    CAS  PubMed  Google Scholar 

  143. van Heel, D. A. et al. Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease. Lancet 365, 1794–1796 (2005).

    Article  CAS  PubMed  Google Scholar 

  144. Yamamoto-Furusho, J. K. & Korzenik, J. R. Crohn's disease: innate immunodeficiency? World J. Gastroenterol. 12, 6751–6755 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kanai, T. et al. Interleukin 18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn's disease. Gastroenterology 119, 1514–1523 (2000).

    Article  CAS  PubMed  Google Scholar 

  146. Chikano, S. et al. IL-18 and IL-12 induce intestinal inflammation and fatty liver in mice in an IFN-γ dependent manner. Gut 47, 779–786 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Ten Hove, T. et al. Blockade of endogenous IL-18 ameliorates TNBS-induced colitis by decreasing local TNF-α production in mice. Gastroenterology 121, 1372–1379 (2001).

    Article  CAS  PubMed  Google Scholar 

  148. Okazawa, A. et al. Human intestinal epithelial cell-derived interleukin (IL)-18, along with IL-2, IL-7 and IL-15, is a potent synergistic factor for the proliferation of intraepithelial lymphocytes. Clin. Exp. Immunol. 136, 269–276 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Takagi, H. et al. Contrasting action of IL-12 and IL-18 in the development of dextran sodium sulphate colitis in mice. Scand. J. Gastroenterol. 38, 837–844 (2003).

    Article  CAS  PubMed  Google Scholar 

  150. Beck, G. & Habicht, G. S. Purification and biochemical characterization of an invertebrate interleukin 1. Mol. Immunol. 28, 577–584 (1991).

    Article  CAS  PubMed  Google Scholar 

  151. Masters, S. L., Simon, A., Aksentijevich, I. & Kastner, D. L. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu. Rev. Immunol. 27, 621–668 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Hoffman, H. M., Mueller, J. L., Broide, D. H., Wanderer, A. A. & Kolodner, R. D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nature Genet. 29, 301–305 (2001).

    Article  CAS  PubMed  Google Scholar 

  153. Aksentijevich, I. et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 46, 3340–3348 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Goldbach-Mansky, R. et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1β inhibition. N. Engl. J. Med. 355, 581–592 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Lachmann, H. J. et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N. Engl. J. Med. 360, 2416–2425 (2009).

    Article  CAS  PubMed  Google Scholar 

  156. Hawkins, P. N., Lachmann, H. J. & McDermott, M. F. Interleukin-1-receptor antagonist in the Muckle–Wells syndrome. N. Engl. J. Med. 348, 2583–2584 (2003).

    Article  PubMed  Google Scholar 

  157. Hoffman, H. M. et al. Efficacy and safety of rilonacept (interleukin-1 trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 58, 2443–2452 (2008).

    Article  CAS  PubMed  Google Scholar 

  158. Aksentijevich, I. et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N. Engl. J. Med. 360, 2426–2437 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Reddy, S. et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N. Engl. J. Med. 360, 2438–2444 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Dierselhuis, M. P., Frenkel, J., Wulffraat, N. M. & Boelens, J. J. Anakinra for flares of pyogenic arthritis in PAPA syndrome. Rheumatology (Oxford) 44, 406–408 (2005).

    Article  CAS  Google Scholar 

  161. Botsios, C., Sfriso, P., Furlan, A., Punzi, L. & Dinarello, C. A. Resistant Behçet disease responsive to anakinra. Ann. Intern. Med. 149, 284–286 (2008).

    Article  PubMed  Google Scholar 

  162. Rigante, D. et al. Treatment with anakinra in the hyperimmunoglobulinaemia D/periodic fever syndrome. Rheumatol. Int. 27, 97–100 (2006).

    Article  PubMed  Google Scholar 

  163. Calligaris, L., Marchetti, F., Tommasini, A. & Ventura, A. The efficacy of anakinra in an adolescent with colchicine-resistant familial Mediterranean fever. Eur. J. Pediatr. 167, 695–696 (2008).

    Article  PubMed  Google Scholar 

  164. Gattorno, M. et al. Persistent efficacy of anakinra in patients with tumour necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 58, 1516–1520 (2008).

    Article  CAS  PubMed  Google Scholar 

  165. de Koning, H. D. et al. Beneficial response to anakinra and thalidomide in Schnitzler's syndrome. Ann. Rheum. Dis. 65, 542–544 (2006).

    Article  CAS  PubMed  Google Scholar 

  166. Picco, P. et al. Successful treatment of idiopathic recurrent pericarditis in children with interleukin-1β receptor antagonist (anakinra): an unrecognized autoinflammatory disease? Arthritis Rheum. 60, 264–268 (2009).

    Article  CAS  PubMed  Google Scholar 

  167. Chen, C. J. et al. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nature Med. 13, 851–856 (2007).

    Article  CAS  PubMed  Google Scholar 

  168. Doz, E. et al. Cigarette smoke-induced pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88 signalling dependent. J. Immunol. 180, 1169–1178 (2008).

    Article  CAS  PubMed  Google Scholar 

  169. Zhang, W. et al. Evidence that hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of interleukin-1β (IL-1β) in astrocyte cultures. J. Neuroimmunol. 174, 63–73 (2006).

    Article  CAS  PubMed  Google Scholar 

  170. Simi, A., Tsakiri, N., Wang, P. & Rothwell, N. J. Interleukin-1 and inflammatory neurodegeneration. Biochem. Soc. Trans. 35, 1122–1126 (2007).

    Article  CAS  PubMed  Google Scholar 

  171. Akuzawa, S. et al. Interleukin-1 receptor antagonist attenuates the severity of spinal cord ischemic injury in rabbits. J. Vasc. Surg. 48, 694–700 (2008).

    Article  PubMed  Google Scholar 

  172. Bujak, M. et al. Interleukin-1 receptor type I signalling critically regulates infarct healing and cardiac remodeling. Am. J. Pathol. 173, 57–67 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Clausen, F. et al. Neutralization of interleukin-1β modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice. Eur. J. Neurosci. 30, 385–396 (2009).

    Article  PubMed  Google Scholar 

  174. Hutchinson, P. J. et al. Inflammation in human brain injury: intracerebral concentrations of IL-1α, IL-1β, and their endogenous inhibitor IL-1ra. J. Neurotrauma 24, 1545–1557 (2007).

    Article  PubMed  Google Scholar 

  175. Olofsson, P. S. et al. A functional interleukin-1 receptor antagonist polymorphism influences atherosclerosis development. The interleukin-1β:interleukin-1 receptor antagonist balance in atherosclerosis. Circ. J. 73, 1531–1536 (2009).

    Article  CAS  PubMed  Google Scholar 

  176. Mallat, Z. et al. Increased plasma concentrations of interleukin-18 in acute coronary syndromes. Heart 88, 467–469 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Blankenberg, S. et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation 106, 24–30 (2002).

    Article  CAS  PubMed  Google Scholar 

  178. Chamberlain, J. et al. Interleukin-1 regulates multiple atherogenic mechanisms in response to fat feeding. PLoS One 4, e5073 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Tenger, C., Sundborger, A., Jawien, J. & Zhou, X. IL-18 accelerates atherosclerosis accompanied by elevation of IFN-γ and CXCL16 expression independently of T cells. Arterioscler. Thromb. Vasc. Biol. 25, 791–796 (2005).

    Article  CAS  PubMed  Google Scholar 

  180. Mallat, Z. et al. Interleukin-18/interleukin-18 binding protein signalling modulates atherosclerotic lesion development and stability. Circ. Res. 89, E41–E45 (2001).

    CAS  PubMed  Google Scholar 

  181. Woldbaek, P. R. et al. Daily administration of interleukin-18 causes myocardial dysfunction in healthy mice. Am. J. Physiol. Heart Circ. Physiol. 289, H708–H714 (2005).

    Article  CAS  PubMed  Google Scholar 

  182. Chandrasekar, B. et al. Activation of intrinsic and extrinsic proapoptotic signalling pathways in interleukin-18-mediated human cardiac endothelial cell death. J. Biol. Chem. 279, 20221–20233 (2004).

    Article  CAS  PubMed  Google Scholar 

  183. Crossman, D. C. et al. Investigation of the effect of interleukin-1 receptor antagonist (IL-1ra) on markers of inflammation in non-ST elevation acute coronary syndromes (The MRC-ILA-HEART Study). Trials 9, 8 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank J. Towne for useful comments on the manuscript.

Author information

Authors and Affiliations

  1. Amgen, 1201 Amgen Court West, Seattle, 98119, Washington, USA

    John E. Sims & Dirk E. Smith

Authors
  1. John E. Sims
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dirk E. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John E. Sims.

Ethics declarations

Competing interests

The authors are employees of Amgen and possess Amgen stock and stock options.

Supplementary information

Supplementary Table 1 (S1)

IL-1 family member knockout mouse phenotypes (PDF 645 kb)

Glossary

Signal peptide

A hydrophobic peptide at the amino terminus of a protein that is recognized by the translocation apparatus and initiates protein translocation from the cytoplasm into the lumen of the endoplasmic reticulum. The signal peptide is typically removed from the mature protein by the signal peptidase during, or subsequent to, translocation.

Inflammasome

A large multiprotein complex formed by a nucleotide-binding domain (NBD)-, leucine-rich repeat (LRR)-containing family (NLR) protein, the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and pro-caspase 1. The assembly of the inflammasome leads to the activation of caspase 1, which cleaves pro-IL-1β and pro-IL-18 to generate the active pro-inflammatory cytokines.

Contact hypersensitivity

A form of delayed-type hypersensitivity (type IV), in which T cells respond to antigens that are introduced through skin contact. It is characterized by monocyte and/or macrophage infiltration and activation, and it depends on the production of TH1-type cytokines.

Histone acetyltransferase

A protein that acetylates core histones, resulting in important regulatory effects on chromatin structure and assembly, which regulates gene transcription.

Heterochromatin

High-density regions in the nucleus that are thought to contain compacted chromatin structures associated with silent genes.

Anaphylaxis

A severe and rapid allergic reaction triggered by the activation of high-affinity Fc receptors for IgE in sensitized individuals. An anaphylactic shock is the most severe type of anaphylaxis and will usually lead to death in minutes if left untreated.

NKT cells

(Natural killer T cells). A heterogeneous subset of T cells, most of which express semi-invariant T cell receptors. In mice, NKT cells were first identified through their expression of the cell surface molecule natural killer cell-associated antigen 1.1 (NK1.1; also known as NKR-P1C).

Regulatory T (TReg) cells

A population of CD4+ T cells that express the transcription factor forkhead box P3 (FOXP3) and have suppressive regulatory activity towards other T cells that are stimulated through their T cell receptor. An absence of regulatory T cells or their dysfunction is associated with severe autoimmunity.

Experimental autoimmune encephalomyelitis

An experimental model of multiple sclerosis that is induced by immunization of susceptible animals with myelin-derived antigens, such as myelin basic protein, proteolipid protein or myelin oligodendrocyte glycoprotein.

γδ T cells

T cells that express the γδ TCR. These T cells constitute the skin, vagina and intestinal epithelium intraepithelial lymphocytes. Although the exact function of γδ T cells is unknown, it has been suggested that mucosal γδ T cells are involved in innate immune responses.

Class switching

The somatic-recombination process by which immunoglobulin isotypes are switched from IgM to IgG, IgA or IgE.

T cell-dependent antibody response

An antibody response to protein antigens that requires recognition of the antigen by helper T cells and cooperation between antigen-specific B and T cells.

Collagen-induced arthritis

A mouse model of polyarticular arthritis that closely resembles rheumatoid arthritis in humans. The disease is induced by immunizing mice with bovine type II collagen.

Rheumatoid arthritis

An autoimmune disease that leads to chronic inflammation in the joints and subsequent destruction of the cartilage and erosion of the bone. It is divided into two main phases: initiation, in which autoimmunity to collagen-rich joint components is established, and the articular phase, which is associated with the evolving destructive inflammatory processes.

Juvenile idiopathic arthritis

The most common rheumatic disease of childhood. It is characterized by local inflammation in the joints, which leads to joint destruction.

Atopic dermatitis

A chronic skin disease in which the skin becomes extremely itchy and inflamed, causing redness, swelling, cracking, weeping, crusting and scaling. Its multifactorial pathogenesis involves genetic susceptibility, environmental triggers and immune dysregulation (typically dominated by TH2 cells), with the involvement of IgE contributing to its classification as an atopic disease.

MRL–lpr mouse

A mouse strain that spontaneously develops glomerulonephritis and other symptoms of systemic lupus erythematosus (SLE). The lpr mutation causes a defect in FAS (also known as CD95), preventing apoptosis of activated lymphocytes. The MRL strain contributes disease-associated mutations that have not been identified.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sims, J., Smith, D. The IL-1 family: regulators of immunity. Nat Rev Immunol 10, 89–102 (2010). https://doi.org/10.1038/nri2691

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2691

This article is cited by

Search

Advanced 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