Interleukins, from 1 to 37, and interferon-γ: Receptors, functions, and roles in diseases

Advancing our understanding of mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections could lead to effective and targeted therapies. Subsets of immune and inflammatory cells interact via ILs and IFNs; reciprocal regulation and counter balance among Th and regulatory T cells, as well as subsets of B cells, offer opportunities for immune interventions. Here, we review current knowledge about ILs 1 to 37 and IFN-γ. Our understanding of the effects of ILs has greatly increased since the discoveries of monocyte IL (called IL-1) and lymphocyte IL (called IL-2); more than 40 cytokines are now designated as ILs. Studies of transgenic or knockout mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided important information about IL and IFN functions. We discuss their signaling pathways, cellular sources, targets, roles in immune regulation and cellular networks, roles in allergy and asthma, and roles in defense against infections. Advancing our understanding of mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections could lead to effective and targeted therapies. Subsets of immune and inflammatory cells interact via ILs and IFNs; reciprocal regulation and counter balance among Th and regulatory T cells, as well as subsets of B cells, offer opportunities for immune interventions. Here, we review current knowledge about ILs 1 to 37 and IFN-γ. Our understanding of the effects of ILs has greatly increased since the discoveries of monocyte IL (called IL-1) and lymphocyte IL (called IL-2); more than 40 cytokines are now designated as ILs. Studies of transgenic or knockout mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided important information about IL and IFN functions. We discuss their signaling pathways, cellular sources, targets, roles in immune regulation and cellular networks, roles in allergy and asthma, and roles in defense against infections. Since the discovery of IL-1 in 1977, approximately 200,000 published articles have referred to ILs. Secreted proteins that bind to their specific receptors and play a role in the communication among leukocytes are named ILs. The nomenclature is continuously evolving, and there have been proposals for the assignment of new members to the IL-1 family.1Dinarello C. Arend W. Sims J. Smith D. Blumberg H. O’Neill L. et al.IL-1 family nomenclature.Nat Immunol. 2010; 11: 973Crossref PubMed Scopus (75) Google Scholar ILs are assigned to each family based on sequence homology and receptor chain similarities or functional properties (Fig 1). CD4+ Th cells are divided into distinct subsets according to cytokine profile. The profile of cytokine expression depends on the adjuvanicity of the molecules presented with the antigen and the status of the T cells, along the types of antigen-presenting cells (APCs) and cytokines in the microenvironment. CD4+ naive T cells can differentiate into Th1, Th2, Th9, Th17, Th22, and T-follicular effector cells. On the basis of their respective cytokine profiles, responses to chemokines, and interactions with other cells, these T-cell subsets can promote different types of inflammatory responses (Fig 2). During the development of allergic disease, effector Th2 cells produce IL-4, IL-5, IL-9, and IL-132Larche M. Akdis C.A. Valenta R. Immunological mechanisms of allergen-specific immunotherapy.Nat Rev Immunol. 2006; 6: 761-771Crossref PubMed Scopus (361) Google Scholar, 3Akdis M. Healthy immune response to allergens: T regulatory cells and more.Curr Opin Immunol. 2006; 18: 738-744Crossref PubMed Scopus (78) Google Scholar; their production of IL-25, IL-31, and IL-33 contributes to Th2 responses and inflammation.4Kang C.M. Jang A.S. Ahn M.H. Shin J.A. Kim J.H. Choi Y.S. et al.Interleukin-25 and interleukin-13 production by alveolar macrophages in response to particles.Am J Respir Cell Mol Biol. 2005; 33: 290-296Crossref PubMed Scopus (65) Google Scholar, 5Dillon S.R. Sprecher C. Hammond A. Bilsborough J. Rosenfeld-Franklin M. Presnell S.R. et al.Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice.Nat Immunol. 2004; 5: 752-760Crossref PubMed Scopus (314) Google Scholar, 6Bilsborough J. Leung D.Y. Maurer M. Howell M. Boguniewicz M. Yao L. et al.IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis.J Allergy Clin Immunol. 2006; 117: 418-425Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 7Kakkar R. Lee R.T. The IL-33/ST2 pathway: therapeutic target and novel biomarker.Nat Rev Drug Discov. 2008; 7: 827-840Crossref PubMed Scopus (175) Google Scholar These cytokines have roles in production of allergen-specific IgE, eosinophilia, and mucus. Th1 cells, however, produce the cytokine IFN-γ, which protects against intracellular pathogens and plays a role in activation-induced death of skin keratinocytes, mucosal epithelial cells, and T cells.8Akdis C.A. Allergy and hypersensitivity: mechanisms of allergic disease.Curr Opin Immunol. 2006; 18: 718-726Crossref PubMed Scopus (56) Google Scholar, 9Akkoc T. de Koning P.J. Ruckert B. Barlan I. Akdis M. Akdis C.A. Increased activation-induced cell death of high IFN-gamma-producing T(H)1 cells as a mechanism of T(H)2 predominance in atopic diseases.J Allergy Clin Immunol. 2008; 121 (e1): 652-658Abstract Full Text Full Text PDF PubMed Scopus (53) Google ScholarFig 2Antigen presentation by DCs to naive T cells and other factors (innate immune response substances, vitamins, cytokines in the environment) induces the T cells to produce ILs and differentiate into Th1, Th2, Th9, Th17, Th22, or follicular Th (TFH) cells. These T-cell subsets can promote different types of inflammatory responses on the basis of their respective cytokine profiles, responses to chemokines, and interactions with other cells.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The discovery of the Th17 has improved our understanding of inflammatory processes. Th17 cells are characterized by their expression of IL-17A, IL-17F, IL-6, IL-8, TNF-α, IL-22, and IL-26.10Burgler S. Ouaked N. Bassin C. Basinski T.M. Mantel P.Y. Siegmund K. et al.Differentiation and functional analysis of human T(H)17 cells.J Allergy Clin Immunol. 2009; 123: 88-95Abstract Full Text Full Text PDF Scopus (61) Google Scholar, 11Harrington L.E. Hatton R.D. Mangan P.R. Turner H. Murphy T.L. Murphy K.M. et al.Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.Nat Immunol. 2005; 6: 1123-1132Crossref PubMed Scopus (2334) Google Scholar The combination of TGF-β and IL-4 reprograms differentiation of Th2 cells so that they become Th9 cells, which produce IL-9 and IL-10.12Veldhoen M. Uyttenhove C. van Snick J. Helmby H. Westendorf A. Buer J. et al.Transforming growth factor-beta “reprograms” the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset.Nat Immunol. 2008; 9: 1341-1346Crossref PubMed Scopus (441) Google Scholar T-follicular helper cells provide helper functions to B cells; they represent one of the largest and most important subsets of effector T cells in lymphoid tissues.13King C. Tangye S.G. Mackay C.R. T follicular helper (TFH) cells in normal and dysregulated immune responses.Annu Rev Immunol. 2008; 26: 741-766Crossref PubMed Scopus (306) Google Scholar Subsets of regulatory T (Treg) cells regulate and counterbalance the immune response; they have distinct phenotypes and mechanisms of action and include CD4+CD25+Forkhead box protein 3 (FoxP3)+ Treg cells, which are selected in the thymus, and type 1 Treg (Tr1) cells, which are induced.14Akdis M. Akdis C.A. Therapeutic manipulation of immune tolerance in allergic disease.Nat Rev Drug Discov. 2009; 8: 645-660Crossref PubMed Scopus (101) Google Scholar, 15Klunker S. Chong M.M. Mantel P.Y. Palomares O. Bassin C. Ziegler M. et al.Transcription factors RUNX1 and RUNX3 in the induction and suppressive function of Foxp3+ inducible regulatory T cells.J Exp Med. 2009; 206: 2701-2715Crossref PubMed Scopus (88) Google Scholar Subsets of CD8+ T cells, γδ T cells, IL-10–producing B cells, IL-10–producing natural killer (NK) cells, dendritic cells (DCs), and macrophages might contribute to immune suppression or regulation.16Taylor A. Verhagen J. Blaser K. Akdis M. Akdis C.A. Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells.Immunology. 2006; 117: 433-442Crossref PubMed Scopus (233) Google Scholar Investigations of the mechanisms of immune and inflammatory cell functions have identified a growing list of ILs and interactions among different cell types that contribute to their effector and suppressive functions (Table I). Detailed information on all cytokines is provided in this article's Online Repository at www.jacionline.org.Table ICharacteristics of cytokinesCytokineStructureSize molecular weightReceptorsCell sourcesCell targetsMajor functionsDisease associationIL-1α, IL-1βHeterodimer17 kdIL-1RI, IL-1RIIMacrophages, monocytes, lymphocytes, keratinocytes, microglia, megakaryocytes, neutrophils, fibroblasts, synovial lining cellsT cells, fibroblasts, epithelial and endothelial cellsInduction of proinflammatory proteins, hematopoiesis, differentiation ofTh17 cellsWide range of autoimmune and inflammatory diseases, RA, IBD, psoriasisIL-1Ra (antagonist)Heterodimer16.1-20 kdIL-1RI, IL-1RIIMonocytes, macrophages, fibroblasts, neutrophils, endothelial and epithelial cells, keratinocytesT cells, fibroblasts, epithelial and endothelial cellsAntagonism of IL-1Wide range of autoimmune and inflammatory diseases, RA, IBD, psoriasisIL-2Monomer15.5 kdIL-2RCD4+ and CD8+ activated T cells, DCs, NK cells, NKT cellsCD4+ and CD8+ T cells, NK and B cellsProliferation of effector T and B cells, development of Treg cells, differentiation and proliferation of NK cells and growth factor for B cellsT-cell–mediated autoimmune and inflammatory diseases, X-linked severe combined immunodeficiency 1IL-3Monomer15 kdIL-3Rα + β c (CD131)T cells, macrophages, NK cells, mast cells, eosinophils, stromal cellsErythroid progenitors, granulocyte-macrophages progenitors, CD34+ progenitor cells, basophils, eosinophilsHematopoietic growth factor, activation of basophils and eosinophilsRole in allergic diseases, different types of cancers, lymphocytic and acute myeloid leukemiasIL-4Monomer15 kdIL-4R type I, IL-4R type IITh2 cells, basophils, eosinophils, mast cells, NKT cells, γ/δ T cells.T and B cellsInduction of Th2 differentiation, IgE class switch, upregulation of class II MHC expression on B cells, upregulation of CD23 and IL-4R, survival factor for B and T cells, role in tissue adhesion and inflammationInflammatory and autoimmune diseases (allergy/asthma and diabetes mellitus), chronic lymphocytic leukemia diseasesIL-5Dimer15 kdIL-5RTh2 cells, activated eosinophils and mast cells, Tc2 cells, γ/δ T cells, NK and NKT cells, CD4– ckit– CD3ε– IL2Rα– (Peyer patches)Eosinophils, basophils, and mast cellsDifferentiation and function of myeloid cells, increment of chemotactic activity and adhesion capacity on eosinophils, remodeling and wound healingAllergy/asthma, hypereosinophilic syndromeIL-6Homodimer19-26 kdIL-6R, (sIL-6R) gp130Endothelial cells, fibroblasts, monocytes/macrophagesHepatocytes, leukocytes, T cells, B cells, hemopoietic cellsLiver: synthesis of acute phase proteins; leukocytes: trafficking, activation; T cell: differentiation, activation, survival; B cell: differentiation, production of IgG, IgM, IgA hematopoiesisAutoimmune disease, chronic inflammatory disease, B-cell malignancy, SLE, Castleman disease, plasmacytoma/multiple myelomaIL-7Monomer25 kdIL-7R and sIL-7REpithelial cells, keratinocytes, DCs, B cells, and monocytes/macrophagesB, T, and NK cellsProliferation of pre-B and pro-B cells (mice), megakaryocytes maturation, VDJ recombinations, naive T-cell survival, synthesis induction of inflammatory mediators in monocytesAllergy/autoimmunity and psoriasisIL-8Homodimer16 kdCXCR1 and CXCR2Monocytes, macrophages, neutrophils, lymphocytes, endothelial cells, epithelial cells, fibroblasts, keratinocytes, chondrocytes, synovial cells, hepatocytesNeutrophils, NK cells, T cells, basophils, eosinophils, endothelial cellsChemoattractant for neutrophils, NK cells, T cells, basophils, eosinophils; mobilization of hematopoietic stem cells; angiogenesisIncreased levels during inflammatory diseases (RA, psoriasis, bacterial and viral infections)IL-9Monomer14 kdIL-9RTh2, Th9, mast cells, and eosinophilsB, T, and mast cellsT and mast cells growth factor, inhibition of Th1 cytokines, proliferation of CD8+ T cells and mast cells, IgE production, chemokine and mucus production in bronchial epithelial cellsHelminth infections, Hodgkin lymphoma, asthma, food allergyIL-10Homodimer20.5 kd, predicted size of precursor protein; 18.6 kd, predicted size mature protein, monomerIL-10R1/IL-10R2 complexT cells, B cells, monocytes, macrophages, DCsMacrophages, monocytes, T cells, B cells, NK cells, mast cells, DC and granulocytesImmune suppressionCancer, autoimmunity, allergyIL-11Monomer19 kdIL-11Rα + gp130Stromal cells: fibroblasts, epithelial cells, endothelial cells, vascular smooth muscle cells, synoviocytes, osteoblastsMyeloid, erythroid, and megakaryocyte progenitors, osteoclasts, epithelial cells, hepatocytes, macrophages, neuronsGrowth factor for myeloid, erythroid, and megakaryocyte progenitors; bone remodeling; protects epithelial cells and connective tissue; induction of acute-phase protein; inhibition of macrophage activity; promotion of neuronal developmentIncreased during allergic asthmaIL-12 (p35/p40)HeterodimerIL-12a p35, 35 kd; IL12b p40, 40 kdIL-12Rb1 and IL-12Rb2Monocytes, macrophages, neutrophils, microglia, DCs, B cellsT cells (Th1 cells), NK cellsInduce Th1-cell differentiation and cytotoxicityImpaired Th1 response with higher susceptibility to intracellular pathogens, use as anticancer agentIL-13Monomer10 kdIL-13R1α1 and IL-13R1α2T, NKT, and mast cells, basophils, eosinophilsB cells, mast cells, epithelial cells, eosinophils, smooth muscle cells and macrophagesSwitching to IgG4 and IgE, upregulation of CD23, MHC-II on B cells, induction of CD11b, CD11c, CD18, CD29; CD23, and MHC-II on monocytes, activation of eosinophils and mast cells, recruitment and survival of eosinophils, defense against parasite infectionsAsthma, allergic rhinitis, fibrosisIL-14Monomer53 kdIL-14RT cells, T-cell clones, B-lineage and T-lineage lymphoma cell linesB cells, certain leukemia cellsProliferation of activated B cellsAutoimmunity, lymphoma genesisIL-15Monomer14-15 kdIL-15RMonocytes, activated CD4+ T cells, keratinocytes, skeletal muscle cellsT, NK, and NKT cellsT-cell activation, proliferation and activation of NK cells, differentiation of γ/δ T cells, suppression of IL-2 induced AICD of T cells, homeostasis of CD8+ memory, NK and NKT cells, enhancement of Th2 differentiation and suppression of allergic rhinitisAutoimmune and inflammatory diseasesIL-16Homotetramer56 kdCD4T cells, eosinophils, mast cells, eosinophils, monocytes, DCs, fibroblasts, epithelial cellsT cells, monocytes, macrophages, eosinophilsChemotaxis, modulation of T-cell responseIncreased during various inflammatory and infectious diseases including atopic eczema, allergic asthma, Crohn disease, RA, hepatitis C infection, tuberculosis; inhibits HIV infectionIL-17ACysteine knot, homodimer or heterodimer35 kdIL-17RA (=IL-17R)Th17 cells, CD8+ T cells, NK cells, NKT cells, γδ T cells, neutrophilsEpithelial/endothelial cells, fibroblasts, osteoblasts, monocytes, macrophagesInduction of proinflammatory cytokines, chemokines, and metalloproteases; recruitment of neutrophilsRA, MS, IBD, psoriasis, allergic asthma, atopic dermatitis, contact hypersensitivityIL-17B,C,DCysteine knot, homodimer41 kd, 40 kd, 52 kdFor IL-17 B, IL-17RB (=IL-17H1, IL25R); for IL-17C and D, not knownIL-17B: neuronal cells, chondrocytes; IL-17C: immune cells under certain conditions; IL-17D: resting B and T cellsMonocytes, endothelial cells, myofibroblastsInduction of proinflammatory cytokines, chemokines, and metalloproteases; IL-17B: chondrogenesis and osteogenesisRA, allergic asthma, inflammatory cardiomyopathy, Wegener granulomaIL-17FCysteine knot, homodimer or heterodimer44 kdIL-17RA (=IL-17R) and IL-17RC (=IL-17RL)Th17 cells, CD8+ T cells, NK cells, NKT cells, γδ T cells, neutrophilsEpithelial/endothelial cells, fibroblasts, osteoblasts, monocytes, macrophagesInduction of proinflammatory cytokines, chemokines, and metalloproteases; recruitment of neutrophilsIBD, psoriasis, allergic asthmaIL-18Heterodimer22.3 kdIL-18RWide range of cells, mainly macrophages, Kupffer cells, keratinocytes, osteoblasts, astrocytes, DCsVariety of cells, T cells, NK cells, macrophages, epithelial cells, chondrocytesInduction of IFN-γ in presence of IL-12, enhances NK cell cytotoxicity, promoting Th1 or Th2–cell responses depending cytokine milieuAutoimmune diseases or inflammatory disorders, RA, psoriasis, MS, type I diabetesIL-19Monomer20.5 kd, predicted size of precursor; 17 kd, predicted size of mature protein; 35-40 kd, found in transfected cells, glycosylatedIL20R1/IL-20R2Monocytes, keratinocytes, airway epithelial cells and B cellsKeratinocytesUnknownPsoriasisIL-20Monomer20 kd, predicted size of precursor; 17.5 kd, predicted size of mature proteinIL-20R1/IL-20R2 and IL-22R1/IL-20R2Monocytes, keratinocytes, epithelial and endothelial cellsKeratinocytes, monocytesRole in skin biologyPsoriasis, RA, atherosclerosisIL-214-Helix bundle, monomer15 kdIL-21RT cells (predominantly Th17), NKT cellsCD4+ T cells, CD8+ T cells, B cells, DCs, macrophages, keratinocytesRegulation of proliferation, differentiation, apoptosis, antibody isotype balance, cytotoxic activityCancer, SLE, RAIL-226 Antiparallel α-helices, monomer23 kdIL-10R2 chain and IL-22R1 chainActivated T cells (predominantly Th17), NKT cells (NK-22)Tissue cells like keratinocytes, subepithelial myofibroblastsPathogen defense, wound healing, tissue reorganizationPsoriasis, IBD, cancerIL-23 (p19+p40)HeterodimerIL-12b p40, 40 kd; IL-23 p19, 19 kdIL-12Rb1 and IL-23RMacrophages, activated DCsT cells (Th17 cells) and macrophagesStimulate production of proinflammatory IL-17 and promote memory T-cell proliferationSusceptibility to extracellular pathogens, exacerbate organ-specific autoimmune inflammationIL-24Homodimer and monomer23.8 kd, predicted size of unprocessed precursor; 18 kd, unglycosylated mature protein; 35 kd, observed size of secreted IL-24, glycosylatedIL20R1/IL-20R2 and IL-22R1/IL-20R2Melanocytes, T cells, monocytesCancer cellsTumor suppressionMelanoma, psoriasisIL-25 (IL-17E)Homodimer17 kdIL-17RA and IL-17RBTh2 cells, mast and epithelial cells, eosinophils and basophils from atopic individualsTh2 memory cellsInduction of Th2 responses, IgE, IgG1, IL-4, IL-5, IL-13, and IL-9 productionGastrointestinal disorders, asthmaIL-266 α-Helices, homodimer38 kdIL-10R2 chain and IL-20R1 chainActivated T cells (predominantly Th17), NKT cellsEpithelial cellsActivation and regulation of epithelial cellsIBDIL-27 (p28+EBI3)HeterodimerIL-27a p28, 28 kd; IL-27b EBI3, 25.4 kdWSX-1 and gp130Activated DCs, macrophages, epithelial cellsT cells, NK cellsInduction of Tbet promoting Th1-cell differentiation, inhibition of Th17-cell response via STAT1Immune pathology because of uncontrolled inflammatory responseIL-28A/B/IL-29 (IFN λ family)MonomerIL-28A, 22.3 kd; IL-28B, 22.2 kd; IL-29, 21.9 kdIL-28R1/IL-10R2Monocyte-derived DCsMost cell typesAntiviral immunityRole in allergic and autoimmune diseasesIL-30 (p28 subunit of IL-27)IL-314-Helix bundle24 kdIL-31RA/OSMRβActivated CD4+ T cells (mainly Th2) and CD8+ T cellsKeratinocytes, epithelial cells, monocytes, eosinophils, basophilsInduction of IL-6, IL-8, CXCL1, CXCL8, CC chemokine ligand 2, and CC chemokine ligand 8 production in eosinophils, upregulates chemokine mRNA expression in keratinocytes, expression of growth factors and chemokines in epithelial cells, inhibition of proliferation and apoptosis in epithelial cellsAtopic dermatitis, allergic contact dermatitis, prurigo nodularis, chronic spontaneous urticaria, nonatopic eczema, asthma, other inflammatory disordersIL-32Unknown14.9-26.6 kdUnknownMonocytes, macrophages, NK cells, T cells, epithelial cellsMacrophages, DCs, T cells, PBMCs, monocytesInduction of TNF-α, IL-8, and IL-6, apoptosisRA, IBD, autoimmune diseasesIL-33β-Trefoil fold30 kd (active form, 18 kd)ST2Necrotic cells and nuocytesBasophils, mast cells, eosinophils, NK cells, NKT cells, Th2 cells, DCs, nuocytesTranscriptional repressor activity, induction of Th2 inflammation on mucosal tissuesAutoimmune and cardiovascular diseases, asthma, gastrointestinal tract and lung disordersIL-34Homodimer39 kd monomersCSF1RHeart, brain, liver, kidney, spleen, thymus, testes, ovary, small intestine, prostate, colon, most abundant in spleenMonocytes, macrophagesProliferationIL-35 (p35+EBI3)Heterodimer60 kdUnknownTreg cellsDifferent T-cell subsetsProliferation of Treg cells and inhibition of Th17-cell function, suppression of inflammatory responsesIBD, collagen-induced arthritisIL-37Unknown17-24 kdIL-18Rα ?Monocytes, tonsil plasma cells, breast carcinoma cellsIntracellular mechanism manner and DCSuppression of proinflammatory cytokines and inhibition of DC activationRAIFN-γHomodimer34 kdIFNGR1/IFNGR2NK and NKT cells, macrophages, myelomonocytic cells, Th1 cells, CTL and B cellsEpithelial cells, macrophages, DCs, NK cells, T and B cellsAntiviral properties, promotes cytotoxic activity, Th1 differentiation, upregulation of MHC class I and II, inhibition of cell growth, proapoptotic effects and control of AICD, regulation of local leukocyte-endothelial interaction, and enhancement of microbial killing abilitySusceptibility to intracellular pathogen infection and tumor development, type 1 diabetes, RA, experimental autoimmune encephalomyelitisAICD, Activation-induced cell death; CTL, cytotoxic T lymphocyte; NK, natural killer; OSMRβ, oncostatin-M receptor β; sIL-6R, soluble IL-6 receptor; STAT1, signal transducer and activator of transcription 1. Open table in a new tab AICD, Activation-induced cell death; CTL, cytotoxic T lymphocyte; NK, natural killer; OSMRβ, oncostatin-M receptor β; sIL-6R, soluble IL-6 receptor; STAT1, signal transducer and activator of transcription 1. IL-1 was first described as a protein that induced fever and was called human leukocytic pyrogen, which is made up of 2 major proteins, IL-1α and IL-1β.17Dinarello C.A. Renfer L. Wolff S.M. Human leukocytic pyrogen: purification and development of a radioimmunoassay.Proc Natl Acad Sci U S A. 1977; 74: 4624-4627Crossref PubMed Google Scholar, 18Dinarello C.A. Immunological and inflammatory functions of the interleukin-1 family.Annu Rev Immunol. 2009; 27: 519-550Crossref PubMed Scopus (916) Google Scholar There are now 11 members of the IL-1 family. Although IL-1α and IL-1β have minimal sequence homology, they have similar biological properties. However, there are fundamental differences in their localization, maturation, and secretion. IL-1α is translated into a biologically active form, whereas IL-1β is translated as pro–IL-1β and has no biological activity until it is processed by caspase-1. IL-1α and IL-1β exert similar effects by binding to the IL-1 type I receptor (IL-1RI). They can also bind to the IL-1 type II receptor (IL-1RII), which acts as a decoy receptor and is not involved in signal transduction. IL-1 is a potent proinflammatory cytokine that acts as an endogenous pyrogen. It has diverse potentiating effects on cell proliferation, differentiation, and function of many innate and specific immunocompetent cells. IL-1 mediates many inflammatory diseases by initiating and potentiating immune and inflammatory responses. The IL-1 receptor antagonist (IL-1Ra) is synthesized and released in response to the same stimuli that lead to IL-1 production.19Eisenberg S.P. Evans R.J. Arend W.P. Verderber E. Brewer M.T. Hannum C.H. et al.Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist.Nature. 1990; 343: 341-346Crossref PubMed Scopus (456) Google Scholar The IL-1Ra lacks the IL-1 receptor accessory protein interacting domain, so that binding of the IL-1Ra to IL-1RI inhibits IL-1 signaling.18Dinarello C.A. Immunological and inflammatory functions of the interleukin-1 family.Annu Rev Immunol. 2009; 27: 519-550Crossref PubMed Scopus (916) Google Scholar There are at least 4 isoforms of the IL-1Ra; 3 isoforms localize within the cell, and the fourth has a signal peptide—it is generally secreted without a requirement for maturation. Therapies under development for some inflammatory disorders involve neutralization of IL-1 activity by administration of IL-1Ra and anti–IL-1 neutralizing mAbs.20Schroder K. Tschopp J. The inflammasomes.Cell. 2010; 140: 821-832Abstract Full Text Full Text PDF PubMed Scopus (969) Google Scholar IL-1Ra–deficient mice spontaneously develop chronic inflammatory polyarthropathy. Balance among the expression levels of IL-1, IL-1Ra, IL-1RI, and IL-1RII is decisive in generation of proinflammatory and/or homeostatic functions.21Horai R. Saijo S. Tanioka H. Nakae S. Sudo K. Okahara A. et al.Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice.J Exp Med. 2000; 191: 313-320Crossref PubMed Scopus (462) Google Scholar IL-18 is a member of the IL-1 family that is expressed by a range of cell types, including macrophages, Kupffer cells, keratinocytes, osteoblasts, astrocytes, and DCs.22Okamura H. Tsutsi H. Komatsu T. Yutsudo M. Hakura A. Tanimoto T. et al.Cloning of a new cytokine that induces IFN-gamma production by T cells.Nature. 1995; 378: 88-91Crossref PubMed Scopus (1891) Google Scholar IL-18 shares structural features with IL-1 and it is synthesized as a 24-kd, biologically inactive precursor that requires cleavage by caspase-1 to become a biologically active molecule.23Arend W.P. Palmer G. Gabay C. IL-1, IL-18, and IL-33 families of cytokines.Immunol Rev. 2008; 223: 20-38Crossref PubMed Scopus (339) Google Scholar The IL-18 receptor (R) complex consists of a heterodimer that contains 2 chains. Although it was originally discovered as an inducer of IFN-γ production, IL-18 alone induces only small amounts of IFN-γ, whereas its combination with IL-12 induces high levels of IFN-γ production by T cells. The biological activity of IL-18 can be neutralized by the IL-18–binding protein, which binds mature IL-18 with a high affinity. IL-18 expression correlates with activities of rheumatoid arthritis (RA) and Crohn disease.23Arend W.P. Palmer G. Gabay C. IL-1, IL-18, and IL-33 families of cytokines.Immunol Rev. 2008; 223: 20-38Crossref PubMed Scopus (339) Google Scholar IL-18–deficient mice are more susceptible to bacterial infections than normal mice and have uncontrolled disease progression that is accompanied by reduced responses of Th1 cells (Table II).24Wei X.Q. Leung B.P. Niedbala W. Piedrafita D. Feng G.J. Sweet M. et al.Altered immune responses and susceptibility to Leishmania major and Staphylococcus aureus infection in IL-18-deficient mice.J Immunol. 1999; 163: 2821-2828PubMed Google ScholarTable IIIn vivo phenotype related to cytokinesCytokinePhenotype of cytokine KO micePhenotype of receptor chain KO micePhenotype of certain transgenicsPhenotype of human polymorphisms and mutationsIL-1α, IL-1βResistance to fever induction, impaired acute-phase responseNormal vigor, no overt phenotypeTransgenic mice overexpressing IL-1α in basal keratinocyte show spontaneous inflammatory skin lesionsPolymorphisms associated periodontal diseasesIL-1ra (antagonist)High susceptibility to develop collagen-induced arthritis, autoimmunity, arteritisNormal vigor, no overt phenotypeProtected from collagen-induced arthritisPolymorphism associated with ulcerative colitis, lupus erythematosus, osteoporosis, and viral infectionsIL-2Reduction of polyclonal T-cell responses, changes of the isotype levels in serum immunoglobulins, absence of secondary antiviral T-cell responses, and reduced NK-cell activityEnlargement of peripheral lymphoid organs associated with polyclonal T-cell and B-cell expansion, development of lymphoproliferative and autoimmune disordersTreg-cell deficiencyDevelopment of X-linked severe combined immunodeficiencyIL-3Abnormal seminal vesicle development; hydrocephalyNormal hematopoiesis, growth, development, and longevity; diminished immunity to parasites (reduced numbers of mast cells)Transgenic mouse expressing antisense IL-3 RNA: death after 3-6 mo of age because of pre–B-cell lymphoproliferative syndrome or neurologic dysfunctionSer27Pro: protective effect on the development of asthmaIL-4Severe trouble on Th2 differentiation, decreases in IgE and IgG1 serum levelsSevere trouble on Th2 differentiation, decreases in IgE and IgG1 serum levelsAllergic airways inflammation and remodelingDevelopment of X-linked severe combined immunodeficiencyIL-5Resistant to induction of experimental asthmaIL-5Rα-/-: low IgM and IgG3 serum concentrationsProlonged wound healing because of increased eosinophilic invasion into the wound areasIL-6Normal (viable, fertile), impaired regulation of T-cell trafficking, abnorma