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  • Review Article
  • Published:

New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions

Nature Reviews Immunology volume 5, pages 521–531 (2005)Cite this article

Key Points

  • The interleukin-6 (IL-6) and IL-12 family of cytokines has an important role in immune regulation in the context of infection and autoimmunity. This article reviews recent studies that have highlighted the unique roles of two of the newer family members, IL-23 and IL-27.

  • Within this grouping of cytokines, the p40 subunit (IL-12p40) is the only component that is shared by two cytokines (IL-12 and IL-23). However, the receptors for IL-12 and IL-23 share the subunit IL-12Rβ1, and the receptors for IL-6 and IL-27 both contain gp130 (glycoprotein 130).

  • IL-12 has an important role in cell-mediated immunity, which is required for resistance to intracellular infections, but experimental data regarding the contribution of IL-12 to the development of autoimmunity have been contradictory.

  • The finding that IL-23 shares a subunit with IL-12 led to the realization that, at least in experimental models, IL-23 and not IL-12 seems to be the main cytokine involved in the development of autoimmunity.

  • The role of IL-23 in the context of infection and autoimmunity seems to be to stimulate a subset of T cells that do not belong to the canonical T helper 1 (TH1) or TH2-cell subset. Instead, these cells express a unique pattern of pro-inflammatory cytokines that is characterized by the secretion of IL-17, IL-6 and tumour-necrosis factor.

  • Initial studies on the immunobiology of IL-27 focused on its ability to promote the development of CD4+ T cells into TH1 cells. Subsequently, it has become clear that this cytokine also has potent inhibitory effects on various immune-cell populations.

  • It seems probable that understanding how the dysregulated expression of these cytokines contributes to immune-mediated disease will provide new opportunities for the development of novel therapeutics.

Abstract

Understanding the factors that influence T helper 1 (TH1)- and TH2-cell responses has been one of the main focuses of immunology for almost 20 years. Whereas the central role of interleukin-12 (IL-12) in the generation of TH1 cells has long been appreciated, subsequent studies indicated that IL-23 and IL-27, two cytokines that are closely related to IL-12, also regulate TH1-cell responses. However, as discussed in this article, it is now recognized that the ability of IL-23 to stimulate a unique T-cell subset to produce IL-17 has a dominant role in autoimmune inflammation. By contrast, IL-27 has a role in limiting the intensity and duration of adaptive immune responses.

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Figure 1: The interleukin-6 and interleukin-12 family of cytokines and their receptors.
Figure 2: Proposed models for the ontogeny of interleukin-17-producing T cells.
Figure 3: The pro- and anti-inflammatory properties of interleukin-27.
Figure 4: Interleukin-27 regulates the intensity and duration of T-helper-1 cell and T-helper-2 cell responses.

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Acknowledgements

I acknowledge the support of friends and colleagues A. Villarino, L. Lieberman, D. Artis, C. Saris, R. Kastelein, F. de Sauvage, H. Yoshida, J. Kolls, N. Ghilardi, G. Trinchieri, J. O'Shea and P. Scott, who have provided crucial insights, and shared unpublished data in this area of research. C.A.H. is supported by a grant from the National Institutes of Health (USA).

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Authors and Affiliations

  1. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, 19104, Pennsylvania, USA

    Christopher A. Hunter

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  1. Christopher A. Hunter
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Competing interests

Christopher Hunter's research group has received support and reagents from Amgen Inc., DNAX Research, Inc. and Genentech, Inc. and has a patent pending on the use of interleukin-27 for modulation of the immune response.

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DATABASES

Entrez Gene

EBI3

gp130

IL-6

IL-6Rα

IL-12p35

IL-12p40

IL-12Rβ1

IL-12Rβ2

IL-17A

IL-17F

IL-23p19

IL-23R

IL-27p28

WSX1

Glossary

FOUR-HELIX BUNDLE

A structural motif in proteins. It consists of four α-helices packed together.

HAEMATOPOIETIN-RECEPTOR DOMAIN

A conserved structural feature of the receptors for type I cytokines. It comprises 200 amino acids that are derived from a tandem of two fibronectin-like domains. The haematopoietin-receptor domain contributes to the cytokine-binding module of these receptors.

ACUTE-PHASE RESPONSE

The early immune response to infection, which results in the production of cytokines and other mediators and in an increase in the number of peripheral leukocytes.

ECZEMATOUS SKIN DISEASE

A clinical process that is associated with severe pathological changes to the skin, which are characterized by redness, oozing, crusting and loss of pigmentation. Histologically, this is characterized by epidermal changes of intracellular oedema, spongiosis or vesiculation.

JAK-STAT

(Janus activated kinase–signal transducer and activator of transcription). An evolutionarily conserved signalling pathway that is associated with type I and type II cytokines. Receptor ligation leads to a series of events that includes the recruitment and activation of JAKs and the phosphorylation of various STATs, which in turn transactivate a variety of genes involved in cell differentiation, survival, apoptosis and proliferation.

EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS

(EAE). An experimental model of the human disease multiple sclerosis. Autoimmune disease is induced in experimental animals by immunization with myelin or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.

COLLAGEN-INDUCED ARTHRITIS

(CIA). An experimental model of rheumatoid arthritis. Arthritis is induced by immunization of susceptible animals with type II collagen.

DELAYED-TYPE HYPERSENSITIVITY

(DTH). A T cell-mediated immune response marked by monocyte and/or macrophage infiltration and activation. DTH skin tests have classically been used for the diagnosis of infection with intracellular pathogens such as Mycobacterium tuberculosis and as a measure of the vigour of the cellular immune system. Classic DTH responses to intracellular pathogens are thought to depend on CD4+ T cells producing a T helper 1 profile of cytokines (that is, interferon-γ and lymphotoxin-α).

T-BET

A member of the Tbox family of transcription factors. It is a master switch in the development of T helper 1 (TH1)-cell responses, through its ability to regulate expression of the interleukin-12 receptor, inhibit signals that promote TH2-cell development and promote the production of interferon-γ.

OXAZOLONE-INDUCED COLITIS

A mouse model of human ulcerative colitis that depends on invariant natural killer T cells and type 2 cytokines.

INVARIANT NATURAL KILLER T CELLS

(Invariant NKT cells). Lymphocytes that express a particular variable gene segment, Vα14 (in mice) and Vα24 (in humans), precisely rearranged to a particular J (joining) gene segment to yield Tcell receptor α-chains with an invariant sequence. Typically, these cells co-express cell-surface markers that are encoded by the NK locus, and they are activated by recognition of CD1d, particularly when α-galactosylceramide is bound in the groove of CD1d.

SARCOIDOSIS

An idiopathic fibrotic disease of humans that has systemic effects. Its pathology is poorly understood, and there are limited treatment options.

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Hunter, C. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol 5, 521–531 (2005). https://doi.org/10.1038/nri1648

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