Reviews and feature articleInterleukins, from 1 to 37, and interferon-γ: Receptors, functions, and roles in diseases
Section snippets
IL-1 and the IL-1 receptor antagonist
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.17, 18 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
Common γ-chain cytokine family
The common γ-chain (γc) family consists of ILs 2, 4, 7, 9, 15, and 21 and was named for binding of these factors to the common γc receptor (CD132; Fig 1). They act mainly as growth and proliferation factors for progenitors and mature cells and also have roles in lineage-specific cell differentiation.
IL-10
IL-10 is an anti-inflammatory factor that is an important regulator of several aspects of immune responses. The IL-10 gene maps to a cytokine cluster that includes the genes IL-19, IL-20, IL-24, and IL-26 on chromosome 1q31-32.52 IL-10 is produced mainly by monocytes, T cells (mainly Tr1 cells), B cells, NK cells, macrophages, and DCs.53 Mast cells can also produce IL-10, which limits the rate of leukocyte infiltration, inflammation, and skin disorders such as contact dermatitis or after
IL-12 family
IL-12, IL-23, IL-27, and IL-35 share receptor and ligand chains (Fig 1). However, their functions differ with their expression on different cell types and combinations of different receptor chains. IL-30 is the alternative designation for the p28 subunit of IL-27.
Th2-like cytokines
Cytokines produced during the induction and function of Th2 response include IL-4, IL-5, IL-9, IL-13, IL-25, IL-31, and IL-33; these mediate immunity against helminth infections, IgE production, and eosinophilia (Fig 2).
IL-8
IL-8 was identified as a neutrophil-specific chemotactic factor and later classified as a member of the CXC chemokine family.127 IL-8 is produced by a variety of cells, such as monocytes and macrophages, neutrophils, lymphocytes, and endothelial and epithelial cells after stimulation with IL-1-α, IL-1-β, IL-17, TNF-α, or TLRs.128 The receptors for IL-8 are CXCR1 (IL-8RA) and CXCR2 (IL-8RB).129 The major effector functions of IL-8 are activation and recruitment of neutrophils to the site of
IL-17 family
IL-17A, initially called IL-17, is the founding member of a structurally distinct cytokine family. It binds as a homodimer or as a heterodimer with IL-17F to its receptor, IL-17RA.139 IL-17A is expressed by activated CD4+ Th17 cells (Fig 2),11 but its expression has also been detected in CD8+ T cells, γδ T cells, NK cells, and neutrophils.139 During Th17 differentiation, human naive T cells must be exposed to IL-1β, IL-6, IL-23, and TGF-β before they express maximum levels of IL-17.10 IL-17RA
IL-3
The human IL-3 gene is on chromosome 5, close to IL-5 and GM-CSF, indicating a common ancestral relationship. It is expressed by T cells, macrophages, stromal cells, NK cells, mast cells, and eosinophils. Because IL-3, IL-5, and GM-CSF share a common receptor subunit β-chain (CD131), their functions partially overlap (Fig 1). On binding IL-3, the β-chain forms a heterodimer with the cytokine-specific α-chain.152 IL-3 is a multilineage hematopoietic growth factor during early stages of
IFN-γ
Cells from the innate (eg, NK cells, NKT cells, macrophages, myelomonocytic cells) and adaptive immune systems (eg, Th1 cells, cytotoxic T lymphocytes, and B cells) produce IFN-γ. A single IFN-γ molecule interacts with 2 ligand-binding IFNGR1 (or IFNGR α) chains and 2 signal-transducing IFNGR2 (or IFNGR β) chains. Each chain is a member of the class II cytokine receptor family.173, 174 High levels of IFN-γ are expressed by Th1 cells, activating macrophages to kill microbes, promoting cytotoxic
Future directions
Several hundred secreted proteins regulate communication among immune system cells and between the immune system and cells of other tissues. Many new cytokines are likely to be categorized as ILs because of recent discoveries. The growing list of ILs requires a better classification strategy and improved understanding of their functions. Categorization according to sequence homogeneity, structure, and common receptor chains is useful, but most ILs do not fit into any particular structural
References (176)
Healthy immune response to allergens: T regulatory cells and more
Curr Opin Immunol
(2006)- 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) Allergy and hypersensitivity: mechanisms of allergic disease
Curr Opin Immunol
(2006)- et al.
The inflammasomes
Cell
(2010) - 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
(2005) - et al.
Identification and initial characterization of four novel members of the interleukin-1 family
J Biol Chem
(2000) - 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-gamma production
Cytokine
(2002) - et al.
Genomic organization of the interleukin-1 locus
Genomics
(2002) - et al.
Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation, and proliferation in CD8 T cells of patients with human immunodeficiency virus-1 (HIV)
Blood
(2007) - et al.
The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29
J Allergy Clin Immunol
(2008)
Mechanisms and treatment of allergic disease in the big picture of regulatory T cells
J Allergy Clin Immunol
IL-10 inhibits CD28 and ICOS costimulations of T cells via src homology 2 domain-containing protein tyrosine phosphatase 1
J Allergy Clin Immunol
Interleukin-10-deficient mice develop chronic enterocolitis
Cell
Interleukin 20: discovery, receptor identification, and role in epidermal function
Cell
Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes
J Biol Chem
IL-22 increases the innate immunity of tissues
Immunity
Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2
J Biol Chem
Expression patterns of IL-10 ligand and receptor gene families provide leads for biological characterization
Int Immunopharmacol
Intratumoral injection of INGN 241, a nonreplicating adenovector expressing the melanoma-differentiation associated gene-7 (mda-7/IL24): biologic outcome in advanced cancer patients
Mol Ther
The T-cell lymphokine interleukin-26 targets epithelial cells through the interleukin-20 receptor 1 and interleukin-10 receptor 2 chains
J Biol Chem
Interferon-lambda-treated dendritic cells specifically induce proliferation of FOXP3-expressing suppressor T cells
Blood
Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12
Immunity
IL-1 family nomenclature
Nat Immunol
Immunological mechanisms of allergen-specific immunotherapy
Nat Rev Immunol
Interleukin-25 and interleukin-13 production by alveolar macrophages in response to particles
Am J Respir Cell Mol Biol
Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice
Nat Immunol
The IL-33/ST2 pathway: therapeutic target and novel biomarker
Nat Rev Drug Discov
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
Differentiation and functional analysis of human T(H)17 cells
J Allergy Clin Immunol
Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages
Nat Immunol
Transforming growth factor-beta “reprograms” the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset
Nat Immunol
T follicular helper (TFH) cells in normal and dysregulated immune responses
Annu Rev Immunol
Therapeutic manipulation of immune tolerance in allergic disease
Nat Rev Drug Discov
Transcription factors RUNX1 and RUNX3 in the induction and suppressive function of Foxp3+ inducible regulatory T cells
J Exp Med
Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells
Immunology
Human leukocytic pyrogen: purification and development of a radioimmunoassay
Proc Natl Acad Sci U S A
Immunological and inflammatory functions of the interleukin-1 family
Annu Rev Immunol
Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist
Nature
Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice
J Exp Med
Cloning of a new cytokine that induces IFN-gamma production by T cells
Nature
IL-1, IL-18, and IL-33 families of cytokines
Immunol Rev
Altered immune responses and susceptibility to Leishmania major and Staphylococcus aureus infection in IL-18-deficient mice
J Immunol
IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex
J Immunol
Activated, but not resting human Th2 cells, in contrast to Th1 and T regulatory cells, produce soluble ST2 and express low levels of ST2L at the cell surface
Eur J Immunol
Innate immunity mediated by the cytokine IL-1 homologue 4 (IL-1H4/IL-1F7) induces IL-12-dependent adaptive and profound antitumor immunity
J Immunol
A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity
Proc Natl Acad Sci U S A
IL-37 is a fundamental inhibitor of innate immunity
Nat Immunol
Selective in vitro growth of T lymphocytes from normal human bone marrows
Science
Structural biology of shared cytokine receptors
Annu Rev Immunol
The biology of interleukin-2
Annu Rev Immunol
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The authors’ laboratories are supported by Swiss National Foundation grants and the Christine Kühne Center for Allergy Research and Education.
Disclosure of potential conflict of interest: M. Akdis has received research support from the Swiss National Foundation and Imvision GmbH. L. O’Mahony has collaborated with Alimentary Health Ltd and has received research support from the Swiss National Science Foundation. C. A. Akdis has received research support from Novartis, Stallergenes, the Swiss National Science Foundation, the Global Allergy and Asthma European Network, and the Christine Kühne Center for Allergy Research and has consulted for Actellion, Aventis, and Allergopharma. The rest of the authors have declared that they have no conflict of interest.