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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).
Dinarello, C. A. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol. 27, 519–550 (2009).
O'Neill, L. A. The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress. Immunol. Rev. 226, 10–18 (2008).
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).
Gabay, C. & McInnes, I. B. The biological and clinical importance of the 'new generation' cytokines in rheumatic diseases. Arthritis Res. Ther. 11, 230 (2009).
Sims, J. E. et al. A new nomenclature for IL-1-family genes. Trends Immunol. 22, 536–537 (2001).
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).
Nicklin, M. J. et al. A sequence-based map of the nine genes of the human interleukin-1 cluster. Genomics 79, 718–725 (2002).
Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229–265 (2009).
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.
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).
Dinarello, C. A. Biologic basis for interleukin-1 in disease. Blood 87, 2095–2147 (1996).
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).
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).
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).
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).
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).
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).
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).
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).
Arend, W. P., Malyak, M., Guthridge, C. J. & Gabay, C. Interleukin-1 receptor antagonist: role in biology. Annu. Rev. Immunol. 16, 27–55 (1998).
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).
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).
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).
Gu, Y. et al. Activation of interferon-γ inducing factor mediated by interleukin-1β converting enzyme. Science 275, 206–209 (1997).
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).
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.
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).
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).
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).
Hayakawa, M. et al. Mature interleukin-33 is produced by calpain-mediated cleavage in vivo. Biochem. Biophys. Res. Commun. 387, 218–222 (2009).
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).
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).
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).
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).
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).
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).
Pan, G. et al. IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp. Cytokine 13, 1–7 (2001).
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).
Sharma, S. et al. The IL-1 family member 7b translocates to the nucleus and downregulates proinflammatory cytokines. J. Immunol. 180, 5477–5482 (2008).
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).
Lin, H. et al. Cloning and characterization of IL-1HY2, a novel interleukin-1 family member. J. Biol. Chem. 276, 20597–20602 (2001).
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).
Wald, D. et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signalling. Nature Immunol. 4, 920–927 (2003).
Bozza, S. et al. Lack of Toll IL-1R8 exacerbates Th17 cell responses in fungal infection. J. Immunol. 180, 4022–4031 (2008).
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).
Suzukawa, M. et al. Interleukin-33 enhances adhesion, CD11b expression and survival in human eosinophils. Lab. Invest. 88, 1245–1253 (2008).
Gudbjartsson, D. F. et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nature Genet. 41, 342–347 (2009).
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).
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).
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).
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).
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.
Wynn, T. A. Basophils trump dendritic cells as APCs for TH2 responses. Nature Immunol. 10, 679–681 (2009).
Yoshimoto, T. & Nakanishi, K. Roles of IL-18 in basophils and mast cells. Allergol. Int. 55, 105–113 (2006).
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).
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).
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).
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).
Chaix, J. et al. Cutting edge: priming of NK cells by IL-18. J. Immunol. 181, 1627–1631 (2008).
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).
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).
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).
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).
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).
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.
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).
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.
O'Sullivan, B. J. et al. IL-1β breaks tolerance through expansion of CD25+ effector T cells. J. Immunol. 176, 7278–7287 (2006).
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).
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.
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).
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).
Wilson, N. J. et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nature Immunol. 8, 950–957 (2007).
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.
Staschke, K. A. et al. IRAK4 kinase activity is required for Th17 differentiation and Th17-mediated disease. J. Immunol. 183, 568–577 (2009).
Atarashi, K. et al. ATP drives lamina propria TH17 cell differentiation. Nature 455, 808–812 (2008).
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).
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).
Brustle, A. et al. The development of inflammatory TH-17 cells requires interferon-regulatory factor 4. Nature Immunol. 8, 958–966 (2007).
Laurence, A. et al. Interleukin-2 signalling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007).
Beriou, G. et al. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 113, 4240–4249 (2009).
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).
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).
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).
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.
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).
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).
Ohshima, Y. et al. Expression and function of OX40 ligand on human dendritic cells. J. Immunol. 159, 3838–3848 (1997).
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).
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).
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).
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).
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).
Mertens, M. & Singh, J. A. Anakinra for rheumatoid arthritis: a systematic review. J. Rheumatol. 36, 1118–1125 (2009).
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).
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).
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).
Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).
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).
Palmer, G. et al. Inhibition of interleukin-33 signalling attenuates the severity of experimental arthritis. Arthritis Rheum. 60, 738–749 (2009).
Xu, D. et al. IL-33 exacerbates antigen-induced arthritis by activating mast cells. Proc. Natl Acad. Sci. USA 105, 10913–10918 (2008).
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).
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).
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).
Schreiber, S. et al. Cytokine pattern of Langerhans cells isolated from murine epidermal cell cultures. J. Immunol. 149, 3524–3534 (1992).
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).
Wang, B. et al. Contribution of Langerhans cell-derived IL-18 to contact hypersensitivity. J. Immunol. 168, 3303–3308 (2002).
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).
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).
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).
Shornick, L. P. et al. Mice deficient in IL-1β manifest impaired contact hypersensitivity to trinitrochlorobenzone. J. Exp. Med. 183, 1427–1436 (1996).
Plitz, T. et al. IL-18 binding protein protects against contact hypersensitivity. J. Immunol. 171, 1164–1171 (2003).
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).
Watanabe, H. et al. Activation of the IL-1β-processing inflammasome is involved in contact hypersensitivity. J. Invest. Dermatol. 127, 1956–1963 (2007).
Lowes, M. A., Bowcock, A. M. & Krueger, J. G. Pathogenesis and therapy of psoriasis. Nature 445, 866–873 (2007).
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).
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).
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).
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).
Gottlieb, A. B. et al. TNF inhibition rapidly downregulates multiple proinflammatory pathways in psoriasis plaques. J. Immunol. 175, 2721–2729 (2005).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Favilli, F. et al. IL-18 activity in systemic lupus erythematosus. Ann. NY Acad. Sci. 1173, 301–309 (2009).
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).
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).
Tanaka, H. et al. IL-18 might reflect disease activity in mild and moderate asthma exacerbation. J. Allergy Clin. Immunol. 107, 331–336 (2001).
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).
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).
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).
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).
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).
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).
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).
van Heel, D. A. et al. Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease. Lancet 365, 1794–1796 (2005).
Yamamoto-Furusho, J. K. & Korzenik, J. R. Crohn's disease: innate immunodeficiency? World J. Gastroenterol. 12, 6751–6755 (2006).
Kanai, T. et al. Interleukin 18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn's disease. Gastroenterology 119, 1514–1523 (2000).
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).
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).
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).
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).
Beck, G. & Habicht, G. S. Purification and biochemical characterization of an invertebrate interleukin 1. Mol. Immunol. 28, 577–584 (1991).
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).
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).
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).
Goldbach-Mansky, R. et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1β inhibition. N. Engl. J. Med. 355, 581–592 (2006).
Lachmann, H. J. et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N. Engl. J. Med. 360, 2416–2425 (2009).
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).
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).
Aksentijevich, I. et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N. Engl. J. Med. 360, 2426–2437 (2009).
Reddy, S. et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N. Engl. J. Med. 360, 2438–2444 (2009).
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).
Botsios, C., Sfriso, P., Furlan, A., Punzi, L. & Dinarello, C. A. Resistant Behçet disease responsive to anakinra. Ann. Intern. Med. 149, 284–286 (2008).
Rigante, D. et al. Treatment with anakinra in the hyperimmunoglobulinaemia D/periodic fever syndrome. Rheumatol. Int. 27, 97–100 (2006).
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).
Gattorno, M. et al. Persistent efficacy of anakinra in patients with tumour necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 58, 1516–1520 (2008).
de Koning, H. D. et al. Beneficial response to anakinra and thalidomide in Schnitzler's syndrome. Ann. Rheum. Dis. 65, 542–544 (2006).
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).
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).
Doz, E. et al. Cigarette smoke-induced pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88 signalling dependent. J. Immunol. 180, 1169–1178 (2008).
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).
Simi, A., Tsakiri, N., Wang, P. & Rothwell, N. J. Interleukin-1 and inflammatory neurodegeneration. Biochem. Soc. Trans. 35, 1122–1126 (2007).
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).
Bujak, M. et al. Interleukin-1 receptor type I signalling critically regulates infarct healing and cardiac remodeling. Am. J. Pathol. 173, 57–67 (2008).
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).
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).
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).
Mallat, Z. et al. Increased plasma concentrations of interleukin-18 in acute coronary syndromes. Heart 88, 467–469 (2002).
Blankenberg, S. et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation 106, 24–30 (2002).
Chamberlain, J. et al. Interleukin-1 regulates multiple atherogenic mechanisms in response to fat feeding. PLoS One 4, e5073 (2009).
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).
Mallat, Z. et al. Interleukin-18/interleukin-18 binding protein signalling modulates atherosclerotic lesion development and stability. Circ. Res. 89, E41–E45 (2001).
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).
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).
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).
Acknowledgements
We thank J. Towne for useful comments on the manuscript.
Author information
Authors and Affiliations
Corresponding author
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
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
Published:
Issue Date:
DOI: https://doi.org/10.1038/nri2691
