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

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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.

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

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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.

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