new il-12-family members: il-23 and il-27, cytokines with divergent functions

© 2005 Nature Publishing Group

Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, Pennsylvania 19104, USA.e-mail: [email protected]:10.1038/nri1648

In 1986, Mosmann, Coffman and colleagues1 described the presence of two types of CD4+ T helper (TH)-cell clone that had distinct profiles of cytokine produc-tion. The TH1-cell subset produced interleukin-2 (IL-2), granulocyte/macrophage colony-stimulating factor and interferon-γ (IFN-γ), whereas the TH2-cell subset secreted a variety of soluble factors that are now recognized as IL-4, IL-5 and IL-13. This seminal observation provided an explanation for the distinct immune responses that are broadly associated with cell-mediated (TH1) and humoral (TH2) immunity dur-ing infection or vaccination2. However, at this point, the events that determined which T-cell subsets dominated an immune response were unclear. IL-12 was identified in 1989, as a soluble factor that could stimulate natural killer (NK) cells to produce IFN-γ3. This discovery paved the way for studies in which it was determined that macrophages and dendritic cells (DCs) produced this heterodimeric cytokine in response to certain bacterial and parasitic infections and that this, in turn, led to the polarization of naive T cells to produce a TH1-cell response4–8. Therefore, IL-12 secretion associ-ated with innate recognition of pathogens was linked with the development of adaptive immune responses dominated by the production of IFN-γ. These events

also seemed to be relevant to other immune-mediated diseases because many experimental and clinical stud-ies implicated IL-12 and IFN-γ in the pathogenesis of autoimmune inflammation9.

The recognition that different CD4+ T-cell subsets could be associated with distinct immunological out-comes indicated that the ability to control polarity or to limit particular types of response could be of use in the design of therapies for infectious or atopic dis-eases. With this aim in mind, one of the main focuses of immunology has been to understand the cellular and molecular events that influence the commitment of naive T cells to TH1- or TH2-cell subsets. Indeed, the discovery of novel cytokines or co-stimulatory molecules that are ligands for receptors expressed by T cells has been accompanied by studies to deter-mine whether they are associated with a particular class of TH cell. Although many immunomodulators were initially linked with one or other subset, it has become apparent that, depending on the context, some have broad effects on T-cell function that are unre-lated to polarity. Two recent examples are IL-23 and IL-27, cytokines that are structurally related to IL-12. Because early work indicated that all three of these cytokines increase the production of IFN-γ by CD4+

NEW IL12FAMILY MEMBERS: IL23 AND IL27, CYTOKINES WITH DIVERGENT FUNCTIONSChristopher A. Hunter

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.

NATURE REVIEWS | IMMUNOLOGY VOLUME 5 | JULY 2005 | 521

REVIEWS

F O C U S O N I M M U N E - C E L L C O M M U N I C A T I O N


Plasmamembrane

Cytokine-receptor homology domain Fibronectin-like domain Immunoglobulin-like domain

p35

p40IL-6

IL-12 IL-27

p28EBI3

p40

p19

IL-23

gp130 IL-6Rα IL-12Rβ1 IL-12Rβ2 gp130 WSX1IL-12Rβ1 IL-23R

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

HAEMATOPOIETINRECEPTOR 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.

ACUTEPHASE 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.

T cells, it made sense to associate the newer members of this family (that is, IL-23 and IL-27) with TH1-cell responses10–12. However, recent studies have revealed that these novel proteins have a limited role in promot-ing classic cell-mediated immunity. Instead, the ability of IL-23 to stimulate CD4+ T cells to produce IL-17 has a dominant role in the development and maintenance of autoimmune inflammation. By contrast, a principal function of IL-27 in vivo is to limit the intensity and duration of innate and adaptive immune responses. The aim of this Review article is to highlight the stud-ies that have uncovered these unexpected functions of IL-23 and IL-27, and to provide a perspective on how these advances have impacted our understanding of infection-induced and autoimmune inflammation.

The IL-6, IL-12, IL-23 and IL-27 familyStructural relationships. The type I cytokines are a superfamily of immunomodulators that are defined on the basis of structural motifs, such as the common FOURHELIX BUNDLE and the HAEMATOPOIETINRECEPTOR

DOMAIN that are common to these ligands and their receptors, respectively13. Many of these factors are involved in the regulation of cell survival, differentia-tion, haematopoiesis and immune function. Thirty-four known type I cytokine receptors have been described, and although the ligands are more difficult to identify, there are at least 27 that can be clustered into 5 distinct families13. One of these groupings is composed of the ligands for a series of cytokine receptors that use gp130 (glycoprotein 130) or one of several gp130-related proteins (FIG. 1). Many of these factors are involved in the development and regulation of immune responses. For instance, IL-6, the canonical member, is closely

associated with the ACUTEPHASE RESPONSE and with the regulation of innate and adaptive immunity14. The receptor for IL-6 contains a unique chain, IL-6Rα, as well as gp130 — a shared component of the receptors for several other family members, including IL-11, leukaemia inhibitory factor, granulocyte colony-stimulating factor and oncostatin M. Consistent with this shared role in signalling mediated by multiple fac-tors, mice that lack gp130 have severe developmental defects15. Although IL-12 was identified as a unique hetero dimeric cytokine, it was recognized that the p35 subunit of IL-12 (IL-12p35) is homologous to type I cytokines, such as IL-6 and oncostatin M, and that the p40 subunit of IL-12 (IL-12p40) is structurally related to the soluble IL-6 receptor (IL-6Rα). The close rela-tionship between IL-6 and IL-12 is further shown by the grouping of the IL-12-receptor components (IL-12Rβ1 and IL-12Rβ2) within the gp130 family of receptors, and this topic is covered in more depth elsewhere11,13.

Although IL-12 remains the prototypical heterodi-meric cytokine, it was not until relatively recently that other related heterodimers were described. In 2000, Kastelein, Bazan and colleagues16 identified the mol-ecule p19 (IL-23p19), on the basis of a homology search for IL-6-family members. Their studies revealed that p19 dimerizes with IL-12p40 and that this cytokine, known as IL-23, uses IL-12Rβ1, but not IL-12Rβ2, as a component of its high-affinity receptor16. Functional cloning of the other subunit of the receptor for IL-23, a subunit known as IL-23R, revealed that mRNA encoding this chain is present in T cells and NK cells and that T-cell activation, regardless of the polarizing conditions, is associated with increased expression of the mRNA encoding this receptor subunit17.

Using a similar approach, a series of important dis-coveries led to the characterization of IL-27 and its recep-tor. On the basis of a homology search for gp130-like proteins, WSX1 (named after the WSXWS protein motif that is found in the carboxyl terminus of many type I cytokine receptors; also known as TCCR) was cloned in 1998 and described as an orphan type I cytokine receptor expressed by NK cells and T cells18. Two years earlier, Epstein–Barr virus (EBV)-induced molecule 3 (EBI3) had been identified as an IL-12p40 homologue secreted by EBV-transformed B cells19, but it was not until 2002 that Kastelein and colleagues20 discovered the p28 subunit of IL-27 (IL-27p28) in a search for proteins with homology to IL-12p35 and IL-6. This observation led to the recognition that IL-27p28 partners EBI3 to form IL-27 and that WSX1 is required for its signalling20. Subsequently, it was established that gp130 is a com-mon element of the receptor for IL-6 (which comprises IL-6Rα and gp130) and the receptor for IL-27 (which comprises WSX1 and gp130), which is consistent with the close familial relationship of these cytokines21.

Given the promiscuous use of receptor and ligand subunits between IL-6, IL-12, IL-23 and IL-27, it is possible that there are additional pairings between these components or interactions with other part-ners. Accordingly, an association between EBI3 and IL-12p35 has been described; however, no distinct

Figure 1 | The interleukin-6 and interleukin-12 family of cytokines and their receptors. Interleukin-6 (IL-6) is a monomeric cytokine that forms a symmetrical complex with gp130 (glycoprotein 130) and the IL-6 receptor α-chain (IL-6Rα), and this complex is required for the propagation of intracellular signals. IL-12 is a covalently linked heterodimer composed of a light chain (IL-12p35) and a heavy chain (IL-12p40). The IL-12 receptor comprises IL-12Rβ1 and IL-12Rβ2, both of which have homology to gp130. The IL-12p40 component of IL-12 can also dimerize with IL-23p19 to form IL-23. The receptor for this heterodimer is formed by the association of IL-12Rβ1 and IL-23R. The last member of this family of cytokines is IL-27, which is composed of EBI3 (Epstein–Barr-virus-induced molecule 3) and IL-27p28. IL-27 binds a receptor composed of gp130 and WSX1. The evolutionary relationship between these cytokines is shown by the homology of IL-12p35, IL-23p19 and IL-27p28 to other single-chain cytokines such as IL-6, whereas IL-12p40 and EBI3 more closely resemble the extracellular domains of members of the haematopoietic cytokine-receptor family, such as IL-6Rα. This similarity indicates that these heterodimeric cytokines are derived from an early precursor of the IL-6 family and from a chain of its receptor.

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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.

JAKSTAT(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.

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

function has been ascribed to this cytokine, and its physiological role remains unclear22. Furthermore, although IL-12p40 and IL-12Rβ1 are shared compo-nents of IL-12- and IL-23-mediated signalling, patients with an IL-12p40 deficiency have an increased mortal-ity rate compared with patients with mutations in the gene encoding IL-12Rβ1 REF. 23. These observations indicate that IL-12p40 might bind subunits other than IL-12p35 or IL-23p19 or that it might be part of a novel cytokine–receptor interaction that is important for resistance to infection. Nevertheless, the recent identification of IL-31, which utilizes a heterodimeric signalling complex composed of a gp130-like molecule (GLMR; also known as IL-31Rα) and the oncostatin-M receptor24,25, indicates that there might be additional interactions between different components of the type I cytokines and their receptors.

Functional relationships. In addition to the structural relationship between IL-6, IL-12, IL-23 and IL-27, there are also elements of the biology of these cytokines that are similar. For example, all of these cytokines are produced in response to microbial and host immune stimuli, such as Toll-like receptors and IFNs16,20,26–28. Furthermore, IL-12p35, IL-23p19 and IL-27p28 are poorly secreted unless co-expressed with their respec-tive partners (that is, IL-12p40 for IL-12p35 and IL-23p19, and EBI3 for IL-27). A probable reason for the tightly regulated secretion of these proteins is that aberrant expression can result in severe inflammation. Consistent with a role for IL-23 in cellular immunity, ubiquitous transgenic expression of IL-23p19 leads to the development of a systemic inflammatory response that is characterized by increased levels of circulat-ing tumour-necrosis factor (TNF) and IL-1 REF. 29. Similarly, transgenic expression of IL-12p40 by basal keratinocytes leads to the development of ECZEMATOUS

SKIN DISEASE30, which is a consequence of dysregulated production of IL-23 REF. 31.

Another common feature of this group of type-I-cytokine-family members is that they activate similar JAKSTAT (Janus activated kinase–signal transducer and activator of transcription)-signalling pathways, a prop-erty that explains some of the overlapping effects on T cells that have been reported. Nevertheless, despite these similarities, the unique functions of these inter-leukins have become more apparent with time. So, whereas many factors coordinate the generation of TH1-cell responses, IL-12 has a central role in pro-moting the differentiation of naive CD4+ T cells into mature TH1 effector cells, and it is a potent stimulus for NK cells and CD8+ T cells to produce IFN-γ32. The importance of this pathway is shown by the numerous studies using mouse models that established that IL-12 is required for the development of protective innate and adaptive immune responses to intracellular pathogens, such as Listeria monocytogenes, Toxoplasma gondii and Leishmania major6,7,33–36. In addition, patients with mutations in IL-12-receptor subunits develop severe infections with mycobacteria and Salmonella spp., indi-cating that, in humans, there is a crucial requirement

for this pathway37,38. Surprisingly, these individuals do not show the same broad range of susceptibility to opportunistic pathogens as IL-12-deficient mice39. This led to the suggestion that other cytokines, such as type I IFNs or other IL-12-family members, have a prominent role in the development of TH1-cell responses in humans. Consistent with this idea, it was reported that IL-23 and IL-27 could promote the production of IFN-γ by human T cells in vitro16,20. Moreover, initial studies with WSX1-deficient mice indicated that there is a role for IL-27 in the genera-tion of TH1-cell responses, and it was proposed that the main role of IL-27 is to direct the early events that lead to the development of TH1-cell responses10,40,41. By contrast, reports that IL-23 increases the proliferation of CD4+ memory T cells and the production of IFN-γ led to a model in which naive T cells are not responsive to IL-23 but activated or memory TH1 cells are sensitive to the effects of this cytokine10–12.

Unique function for IL-23 in T-cell responsesAs a consequence of the structural and functional simi-larities between IL-12 and IL-23, it seemed probable that IL-23, similar to IL-12, would also have a func-tion in the regulation of TH1-cell responses. However, it is now apparent that these two immunomodulators have discrete roles in the regulation of T cells during infection and autoimmunity.

IL-23 in autoimmune inflammation. As noted earlier, IL-12 has an established role in promoting IFN-γ pro-duction and thereby resistance to intracellular infec-tions, but there was also evidence that similar TH1-cell responses contributed to autoimmunity in animal models of diabetes, colitis, multiple sclerosis, arthritis and uveitis9. The use of IL-12p40-deficient mice or neutralizing antibodies specific for IL-12p40 subse-quently established that this subunit is essential for the development of T-cell mediated diseases, such as EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS (EAE), COLLAGEN

INDUCED ARTHRITIS (CIA) and inflammatory bowel disease (IBD)42–45 TABLE 1. However, although the inflammatory response in these models was charac-terized by the production of IFN-γ, the role of IFN-γ in the development of inflammation is less clear. This is shown by the finding that IL-12p40 is important for the development of central nervous system (CNS) inflammation during EAE but that mice lacking IFN-γ-mediated signalling remain susceptible to this condi-tion and develop more severe pathology46–48. Similarly, during CIA, treatment with IL-12p40-specific antibod-ies prevented disease, but the absence of IFN-γ or the IFN-γ receptor resulted in increased arthritic scores49. Furthermore, use of IL-12p40- or IFN-γ-specific anti-bodies antagonized the development of spontaneous IBD in IL-10-deficient mice, but only neutralization of IL-12p40, not IFN-γ, ameliorated established colitis50. The discrepancy between the role of IL-12p40 and IFN-γ in these models of inflammation was inconsis-tent with a linear model in which IL-12 drives a patho-logical autoimmune TH1-cell response, and it indicated




DELAYEDTYPE 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).

that the ability of IL-12 to promote T-cell proliferation and survival might be important in these experimental systems.

Although IL-12p40 has an important role in the development of pathological T cells, comparative studies of IL-12p40-deficient mice and IL-12p35-deficient mice revealed an unexpected dichotomy. In EAE, IL-12p40-deficient mice do not develop disease, whereas IL-12p35-deficient mice (similar to IFN-γ-deficient mice) show more severe pathology than wild-type animals51,52 TABLE 1. The finding that IL-12p40 is a shared component of IL-12 and IL-23 led to the realization that the latter cytokine might account for this disparity. Furthermore, the finding that stimula-tion of activated and/or memory T cells in the pres-ence of IL-23 (but not IL-12) led to the production of IL-17 BOX 1, but not IFN-γ or IL-4, provided the first evidence of a unique role for IL-23 in the regulation of a T-cell effector function53. Nevertheless, it was not until the generation of mice that lacked the IL-23-specific component IL-23p19 that it was possible to distin-guish the roles of IL-12 and IL-23 in vivo. In the first reports of studies using these mice, it was established that IL-12p40 and IL-23p19, but not IL-12p35, have an essential role in the development of EAE54. So, IL-23, not IL-12, is essential for the development of this auto-immune condition. Because macrophages and DCs are responsive to IL-23, it was initially proposed that macrophages and microglia within the CNS were tar-gets of IL-23 and that this interaction stimulated local production of TNF by these cells54. However, the use of encephalitogenic T cells in an adoptive-transfer system revealed that IL-23 does not promote the development of TH1-cell responses — but, instead, induces a subset of T cells with a unique cytokine expression pattern (IL-6, IL-17A, IL-17F and TNF) — and that these cells are suf-ficient to induce neurological disease55. Consistent with

this result, blockade of IL-17A alone, but not IFN-γ, decreases the severity of clinical disease in this model. Similarly, studies of CIA revealed that the absence of IL-12p35 leads to exacerbated arthritis, whereas IL-23-deficient animals are resistant to the development of bone and joint pathology56. These latter findings56 correlate with an absence of CD4+ T cells that produce IL-17, a cytokine with an important role in the devel-opment of arthritic disease57,58. Moreover, mice that lack IL-23 are deficient in DELAYEDTYPE HYPERSENSITIVITY responses, which is consistent with a reduced capac-ity to produce IL-17 REF. 59. Although these results clarify the role of the IL-23–IL-17 pathway in auto-immune inflammation, they do not directly explain the enhanced disease that is associated with the absence of IFN-γ or IFN-γ-mediated signalling in animals with EAE or CIA. These latter observations have led to the idea that IFN-γ is part of a regulatory system that counterbalances the effects of IL-23 REF. 60 (FIG. 2).

IL-23 in infectious disease. As a clearer picture of the contribution of IL-23 to autoimmunity has begun to emerge, it has also become apparent that much less is known about its role in resistance or susceptibility to infection. Indeed, for many years, it was considered that IL-12p40 was only involved in the production of IFN-γ during infection. Unlike the disparities in susceptibil-ity to EAE and CIA between mice that lack IL-12p40 and mice that lack IFN-γ, many studies have shown that IL-12p40-deficient mice and IFN-γ-deficient mice have similar patterns of susceptibility when infected with a range of viral, bacterial and parasitic patho-gens61. For example, direct comparison of IL-12p40-deficient mice and IL-12p35-deficient mice infected with L. major revealed that these mouse strains are equally susceptible to this parasite and that both fail to generate protective TH1-cell responses62,63. However, as

Table 1 | Inflammatory phenotypes associated with IL-12, IL-23 and IL-27

Mouse genotype Mouse phenotype References

Il-12p40 knockout Susceptible to infection with several intracellular pathogensResistant to developing adjuvant-induced autoimmunity

42,51,52,54,56,62–69

Il-12p40 transgenic Develop inflammatory skin lesions 30,31

Il-12p35 knockout Deficient in TH1-cell responses, but more resistant to some intracellular pathogens than Il-12p40-knockout miceIncreased disease severity of EAE and CIA

51,52,54–56,62–69

Il-23p19 knockout Defect in DTH responsesResistant to developing EAE and CIA

54–56,59

Il-23p19 transgenic Develop systemic inflammatory disease 29,31

gp130 knockout Severe developmental defects 15

gp130 knock-in* Aberrant inflammatory responses in the gastrointestinal tract 127

Wsx1 knockout Transient defect in TH1-cell responses during leishmaniasisIncreased T-cell proliferation and pathological T-cell responses in several models of infection and inflammation

40,41,90,101–106

Ebi3 knockout Transient defect in TH1-cell responses during leishmaniasisMore resistant to oxazolone-induced colitis

91,100

*These mice are also deficient in STAT (signal transducer and activator of transcription) or SHP2 (SRC-homology-2-domain-containing protein tyrosine phosphatase 1) signalling. CIA, collagen-induced arthritis; DTH, delayed-type hypersensitivity; EAE, experimental allergic encephalomyelitis; Ebi3, Epstein–Barr-virus-induced molecule 3; gp130, glycoprotein 130; Il-12p35, interleukin-12 p35 subunit; Il-12p40, interleukin-12 p40 subunit; Il-23p19, interleukin-23 p19 subunit; TH1, T helper 1; Wsx1, subunit of interleukin-27 receptor.


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more comparative studies have been carried out, it has become evident that there is an IL-12p40-dependent, IL-12p35-independent mechanism of resistance to sev-eral microorganisms, including Francisella tularensis, Filobasidiella neoformans (Cryptococcus neoformans), Salmonella enteritidis, Mycobacterium spp., T. gondii and mouse cytomegalovirus64–69. In some of these cases, the differences between IL-12p40-deficient mice and IL-12p35-deficient mice are subtle, manifested as tis-sue-specific changes in parasite or bacterial burdens, or increased early resistance to challenge with avirulent strains or slow-growing pathogens. At present, the basis for these observations remains uncertain, but there is evidence that IL-12p40 monomers or dimers might enhance cell-mediated immunity67. Alternatively, because IL-12p40 can dimerize with IL-23p19, this indicates that the production of IL-23 might bet-ter explain the presence of an IL-12p40-dependent, IL-12p35-independent mechanism of resistance to these diverse infections.

Although comparison of the phenotypes of IL-12p40-deficient mice and IL-12p35-deficient mice indicated a role for IL-23 in resistance to several pathogens, studies using the Gram-negative bacterium Klebsiella pneumoniae have provided some of the best insights into the role of IL-23 during infection. Previous reports have established that IL-17 has an important role in resistance to this pathogen70, and in vitro studies have shown that K. pneumoniae-pulsed DCs produce IL-23, which leads to the production of IL-17 by CD4+ and CD8+ T cells71. Furthermore, in the absence of IL-12p35, mice infected with K. pneumo-niae fail to generate pulmonary IFN-γ but show normal

induction of IL-17 expression; by contrast, IL-23p19-deficient mice infected with K. pneumoniae develop normal IFN-γ responses but cannot produce IL-17 and, as a consequence, have increased susceptibility to this pathogen (J. Kolls, personal communication). These studies establish that IL-23 is important during challenge with K. pneumoniae, and they indicate that IL-12 and IL-23 have distinct roles in resistance to this bacterium. There is also evidence that the IL-23–IL-17 pathway is relevant during other infections. When IL-17-receptor-deficient mice are challenged with T. gondii, they have reduced neutrophil responses and higher parasite burdens72. However, infection of IL-23p19-deficient mice with T. gondii has not revealed any obvious defects in acute responses to this parasite. Nevertheless, administration of IL-23 to IL-12p40-deficient mice does result in increased resistance to toxoplasmosis69, but it is unclear whether this is a con-sequence of its ability to stimulate the production of IL-17 or of other cytokines, such as IL-6 and TNF, that are known to promote resistance to this intracellular organism73–76.

Mediators of the inflammatory effects of IL-23. Together, the studies described in the previous sec-tions have led to a new model in which IL-23 stimu-lates a unique subset of T cells to produce IL-17, and these T cells, in turn, induce the production of pro-inflammatory cytokines, which contribute to auto-immunity or protective responses during infection60 (FIG. 2). The identification of this pathway has resulted in questions about the ontogeny of these pathological CD4+ T cells and the factors that regulate their activi-ties. It is probable that the relative amounts of IL-12 and IL-23 might determine whether T-cell production of IL-17 or IFN-γ dominates. However, although there are studies that show differential production of these cytokines in response to various microbial and immune stimuli, there is a limited appreciation of the events that influence the amounts of these cytokines in vivo. In addition, because IL-12Rβ1, the shared component of the receptors for IL-12 and IL-23, is constitutively expressed by CD4+ T cells, it is probable that selective expression of IL-12Rβ2 or IL-23R controls sensitiv-ity to these factors. In current models, it is proposed that IL-12Rβ2 is expressed at a low level or is absent from naive and memory CD4+ T cells and that, only after antigen encounter, are high levels of this recep-tor chain expressed. By contrast, it seems that IL-23R is absent from naive and effector T cells but that high levels are present at the cell surface of memory T cells. However, given that IL-23 stimulates the production of a distinct profile of cytokines, it could be that the distribution pattern of IL-23R is more complex than has previously been appreciated. The development of reagents to reliably follow cell-surface expression of IL-12Rβ2 and IL-23R will provide a more complete picture of whether the receptors for IL-12 and IL-23 are co-expressed or whether they are expressed at the surface of distinct effector T-cell subsets or varied accessory cell populations.

Box 1 | The interleukin-17 family of cytokines

There are six members of the interleukin-17 (IL-17) family (IL-17A, -B, -C, -D, -E and -F). These homodimeric cytokines are implicated in the regulation of local inflammation at multiple sites but most markedly in the intestine, lungs and joints. There are five components of the IL-17-receptor family, some of which exist as splice variants that can form heterodimers. The prototypical IL-17 receptor binds both IL-17A and IL-17F, and recent attention has focused on the role of IL-17A and IL-17F in the regulation of autoimmunity, as well as in the immune response to bacterial infections and cancer. Activated or memory CD4+ and CD8+ T cells are some of the main sources of IL-17A and IL-17F, but the expression of these cytokines does not seem to be restricted to cells with a T helper 1 (TH1) or TH2 profile. Production of IL-23 is an important pathway that leads to the production of IL-17A and IL-17F, although other cytokines, including IL-15, have also been implicated in this process. Although T cells have been reported to express the IL-17 receptor, endothelial cells and macrophages seem to be the main targets for IL-17A and IL-17F. IL-17A and IL-17F alone, or in synergy with tumour-necrosis factor, can stimulate endothelial cells and macrophages to produce several factors that regulate local inflammation. These include the following: CXC-chemokines, notably CXC-chemokine ligand 8 (CXCL8; also known as IL-8) and CXCL6 (also known as GCP2); granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor, which are involved in granulopoiesis; and the pro-inflammatory cytokines IL-1, IL-6 and tumour-necrosis factor. IL-17E (also known as IL-25) is the most divergent family member, and it has been associated with TH2-cell responses, although its receptor is unknown. Overexpression of this cytokine results in eosinophilia associated with enhanced type 2 immune responses, but increased interferon-γ responses can also be observed in some experimental systems. More comprehensive discussion of this topic is provided in REF. 131.




IL-12Rβ1

IL-12

IL-12

IL-12Rβ2

IL-12Rβ1

IL-12Rβ1

IL-12

IL-12Rβ2

IL-12Rβ1

IL-12Rβ1

IL-12

NaiveCD4+ T cell

IL-12Rβ2

IL-12Rβ1 IL-12

IL-23

IFN-γ

TH1 cell

IFN-γ

IL-17

IL-6

TNF

IL-17-producing T cell

IL-17

IL-6

TNF

IL-17

IL-6

TNF

IL-23

IL-23

IL-23R

IL-23

IL-23R

IL-23

IL-23R

IL-23IL-12

IL-12Rβ1

IL-12Rβ1

IL-12Rβ1

a

b

c

TBET A member of the T-box 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.

There also remain several questions about the ontog-eny of IL-17-producing T cells during auto immune processes. Stimulation of naive T cells with IL-23 alone is not a strong inducer of a de novo population of IL-17- producing T cells in vitro55. Moreover, T cells from IL-23p19-deficient mice can still produce IL-17 when restimulated in the presence of IL-23 REF. 56. Together, these findings imply that IL-23 is not essential for the generation of these cells, and it seems probable that other factors are required to promote the develop-ment of this unique T-cell subset. Alternatively, because these cells also produce low levels of IFN-γ, it has been proposed that pre-existing TH1 cells might be the source of this unique effector population77. By contrast, it has been proposed that TH1-cell responses antago-nize the IL-23–IL-17 pathway during autoimmunity60. Nevertheless, IFN-γ and IL-17 might work together to increase resistance to infectious diseases. For example, although IL-23 and IL-17 have a role in resistance to infection with K. pneumoniae and T. gondii, protection against these organisms also depends on cytokines and transcription factors that are associated with clas-sic TH1-cell responses (such as IL-12, IFN-γ, inducible

nitric-oxide synthase and STAT4)34,78–84. Similarly, there is evidence that IL-17 and IFN-γ synergize to increase keratinocyte production of pro-inflammatory cytokines, and this might be important in the develop-ment of inflammation at dermal sites85. Nevertheless, at present, there is a paucity of information about how IL-23-deficient mice respond to pathogens and whether T cells that produce IFN-γ and/or IL-17 work together to induce appropriate protective immunity.

IL-27: pro- and anti-inflammatory effectsAlthough many type I cytokines have been character-ized on the basis of their pro-inflammatory effects, it has become clear that several of these proteins also have immunosuppressive properties. So, despite the scientific literature describing a role for IL-27 in the development of TH1-cell responses, there is compelling evidence that this immune factor can also antagonize effector T-cell responses (FIG. 3).

Pro-inflammatory properties of IL-27. Because IL-27 is homologous to IL-12 and because, similar to the IL-12 receptor, the IL-27 receptor is present at the surface of CD4+ T cells, initial investigations focused on whether IL-27 influences TH1-cell responses. Early reports showed that IL-27 increases the production of IFN-γ by naive CD4+ T cells and that IL-27-receptor-deficient T cells produce less IFN-γ in vitro than wild-type T cells40,41. Consistent with these observations, signalling through the IL-27 receptor can activate STAT1 and thereby promote expression of TBET — a transcription factor, the target genes of which include genes encoding signature components of TH1-cell responses, IL-12Rβ2 and IFN-γ86–89 (FIG. 3). Together with reports that T-cell activation results in the downregulation of IL-27-receptor expression40, these findings indicated a model in which IL-27 sen-sitizes naive CD4+ T cells to the TH1-cell polarizing effects of IL-12 REF. 10 (FIG. 4). Accordingly, initial studies using IL-27-receptor-deficient mice indicated that these mice were more susceptible to infection with L. monocytogenes40, although after backcrossing these mice onto a more defined genetic background, these differences are less apparent (F. de Sauvage, per-sonal communication). Nevertheless, these mice do show an early susceptibility to L. major that is associated with increased TH2-cell responses and reduced genera-tion of TH1 cells39. However, at later time points, mice that lack the IL-27 receptor or the EBI3 component of IL-27 develop Leishmania-specific TH1 cells and con-trol this infection, and pretreatment of mice deficient in WSX1 (a subunit of the IL-27 receptor) with IL-4-specific antibodies reverses this early susceptibility90,91. Taken together, these studies indicate that the require-ment for IL-27 in the development of protective immu-nity during leishmaniasis is transient. This conclusion is in agreement with the finding that IL-27 is not required to promote IFN-γ responses in most other experimental systems in which it has been examined92.

Although there is limited evidence of a role for endogenous IL-27 in promoting cellular responses

Figure 2 | Proposed models for the ontogeny of interleukin-17-producing T cells. At present, little is known about the relationship between T helper 1 (TH1) cells and interleukin-17 (IL-17)-producing T cells. It is clear that naive CD4+ T cells constitutively express the IL-12-receptor chain IL-12Rβ1 but express only low or negligible levels of IL-12Rβ2 or the IL-23-receptor chain IL-23R. In response to appropriate activation, these receptors are upregulated, but it remains unclear whether they are co-expressed (a) or whether there are exclusive patterns of expression (b). In the first scenario, the availability of IL-12 or IL-23 determines which T-cell subset dominates. In the second scenario, receptor expression ‘licenses’ T cells to produce interferon-γ (IFN-γ) or IL-17. Another alternative is also possible, and this is outlined here as a linear model in which naive CD4+ T cells become responsive to IL-12, develop into long-lived TH1 cells and then downregulate expression of IL-12Rβ2 but begin to express IL-23R (c). When exposed to IL-23 these TH1 cells then produce high levels of IL-17, IL-6 and tumour-necrosis factor (TNF).


R E V I E W S


IFN-γIFN-γ

ProliferationProliferation

L. major, T. gondii, T. cruzi,T. muris, Mycobacterium spp.or concanavalin A

APC

IL-27Pro-inflammatory

gp130

CD4+ T cell

WSX1

IL-27

Anti-inflammatory

IL-4and IL-5

STAT1, STAT4,T-bet

STAT3, STAT5

STAT1, STAT3

STAT1, STAT5

GATA3

IFN-γ

Cytotoxicity

CD8+ T cell

NK cell

STAT1, STAT4,T-bet

IFN-γSTAT1, STAT4,T-bet

STAT1, STAT4

IFN-γ STAT1, STAT3, T-bet

IFN-γ

Proliferation

STAT1, STAT3

STAT1, STAT5

Mastocytosis anddegranulation STAT3

Mast cell

STAT3

IL-6 andTNF

Monocyte

IL-1, IL-12,IL-18 and TNF

STAT1, STAT3 STAT1, STAT3

IL-1 andTNF

OX40 andRANKL

during infection, there are studies indicating that it can promote inflammation in models of autoimmunity and cancer. Transgenic overexpression of IL-27 during viral hepatitis or by mouse carcinomas leads to increased CD8+ T-cell IFN-γ production, cytotoxicity and tumour clearance93–96 (FIG. 3). Although these studies support the idea that IL-27 can promote CD8+ T-cell responses, there are reports that tumour cells might themselves be targets of IL-27 REF. 97. In addition, there are reports that the severity of adjuvant-induced arthritis in rats and EAE in mice can be ameliorated by IL-27-specific antibodies98,99. In the latter model, treatment of CD4+ T cells specific for the autoantigen myelin oligodendrocyte glyco protein with their cognate ligand plus IL-27p28 resulted in marked increases in the production of IFN-γ and TNF, and in increased proliferative responses99. Moreover, it is clear that the ability of IL-27 to promote inflammation is not restricted to its role in promoting IFN-γ responses. So, mice that lack EBI3 are resistant to OXAZOLONEINDUCED

COLITIS, but the lack of disease has been attributed to an absence of INVARIANT NATURAL KILLER T NKT CELLS100. Other reports show that IL-27 can directly induce mast cells and monocytes to produce IL-1 and TNF21 (FIG. 3), but these observations are in contrast to studies indicating that IL-27 is a negative regulator of mast-cell and macro-phage function101–103 (FIG. 3). Nevertheless, these findings highlight the need for additional studies to understand when these pro-inflammatory effects of endogenous IL-27 are of biological significance.

Anti-inflammatory properties of IL-27. The first data indicating that IL-27 has anti-inflammatory effects were provided by in vivo models of parasitic infection. In par-ticular, studies by Villarino and colleagues104 revealed that WSX1-deficient mice infected with T. gondii develop normal CD4+ and CD8+ T-cell IFN-γ responses during the acute phase of infection and these responses are sufficient to control parasite replication. However,

Figure 3 | The pro- and anti-inflammatory properties of interleukin-27. Interleukin-27 (IL-27) expression is induced in response to various inflammatory stimuli and can affect many elements of innate and adaptive immune responses. Its pro-inflammatory effects are exemplified by its ability to promote effector responses of CD4+ and CD8+ T cells, as well as natural killer (NK) cells. In addition, the ability of IL-27 to stimulate mast cells and monocytes to produce pro-inflammatory cytokines and to express activating receptors supports an inflammatory role for this cytokine. The anti-inflammatory effects of IL-27 are shown by the increased T-cell and NK-cell responses that are observed in the absence of the IL-27-receptor subunit WSX1 in numerous models of infection, as well as by the ability of IL-27 to directly inhibit these effects in vitro. Similarly, the absence of the IL-27 receptor leads to increased mast-cell and macrophage responses following microbial challenge in vivo, indicating that IL-27 also suppresses these activities. APC, antigen-presenting cell; GATA3, GATA-binding protein 3; gp130, glycoprotein 130; IFN-γ, interferon-γ; L. major, Leishmania major; RANKL, receptor activator of nuclear factor-κB ligand; STAT, signal transducer and activator of transcription; T. cruzi, Trypanosoma cruzi; T. gondii, Toxoplasma gondii; T. muris, Trichuris muris; TNF, tumour-necrosis factor.




NaiveCD4+ cell

IL-2

IL-27

TH1 cell

TH1-cell clonalexpansion

TH2-cell clonalexpansion

TH2 cell

gp130 WSX1

IL-27

IL-12

IL-4

IL-2

OXAZOLONEINDUCED 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 Jα (joining) gene segment to yield T-cell 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.

these mice fail to downregulate the adaptive immune response and develop a lethal CD4+ T-cell-dependent inflammatory disease104. This pathological response was shown to be intrinsic to the T cells and is charac-terized by increased proliferation of T cells, increased production of IFN-γ and IL-2, and maintenance of a population of highly activated (CD25+CD62Llow) CD4+ and CD8+ T cells. Similarly, Yoshida and colleagues101 showed that, during infection with Trypanosoma cruzi, WSX1-deficient mice develop exaggerated T-cell responses, together with increased production of inflammatory cytokines, including IL-4, IL-6, TNF and IFN-γ101. Correspondingly, when compared with wild-type animals, WSX1-deficient mice show increased sensitivity to concanavalin A (conA)-induced hepatitis that correlates with increased production of IL-4 and IFN-γ by NKT cells105. Furthermore, IL-27-receptor-deficient mice infected with Mycobacterium tuberculosis have a lower bacterial burden than their wild-type counterparts, develop more severe lung pathology and succumb to this infection103,106, presumably as a conse-quence of immune-mediated pathology. Together, these studies imply that, in the presence of strongly polarizing stimuli, such as parasitic or bacterial infections, the ability of IL-27 to promote TH1-cell responses becomes secondary to its role as a suppressor of effector T-cell proliferation and cytokine production (FIG. 4). Although this idea is inconsistent with models in which only naive T cells are sensitive to IL-27, a more detailed analysis of WSX1 expression has revealed that naive T cells have low surface levels of this subunit and that the highest levels are present at the surface of antigen-experienced T cells107. So, it is probable that IL-27 can influence the function of multiple T-cell subsets, including naive, effector, regulatory and memory T cells107.

The reports discussed here indicate that IL-27-receptor signalling can inhibit infection-induced TH1 effector cells, but there is also evidence of increased TH2-cell responses in IL-27-receptor-deficient mice challenged with L. major, T. cruzi or conA92. However, because IL-27 can promote IFN-γ production, which in turn can inhibit the development of TH2 cells, it has been difficult to distinguish whether these heightened TH2-cell responses are a consequence of reduced numbers of TH1 cells or of a direct inhibitory effect of IL-27 on TH2-cytokine production. Studies using the parasitic nematode Trichris muris have begun to dissect this issue and indicate a direct regulatory role for IL-27 in these events. During infection, WSX1-deficient mice develop accelerated TH2-cell responses and, con-sequently, show early expulsion of larval worms102,108. Given that wild-type animals do not acquire this hyper-resistant phenotype when TH1-cell responses are blocked in vivo, it is unlikely that the increased produc-tion of IL-4, IL-5 and IL-13 in the WSX1-deficient mice is a secondary consequence of an intrinsic defect in the production of IFN-γ102. Moreover, WSX1-deficient CD4+ T cells produce more IL-5 and IL-13 than their wild-type counterparts during differentiation into TH2 cells in vitro, and IL-27 can directly inhibit CD4+ T-cell production of IL-4 REF. 102, in part by suppressing their expression of GATA3 (GATA-binding protein 3) — a transcription factor that promotes TH2-cell lineage commitment88 (FIG. 3).Therefore, it seems that IL-27 has a direct inhibitory effect on the generation of TH2-cell responses that is independent of its ability to enhance IFN-γ production.

Effects of IL-27 on T-cell proliferation. Together, the reports discussed here indicate that IL-27 can regulate the kinetics and intensity of T-cell responses and that these effects are not restricted to a particular TH-cell subset92. To understand this activity of IL-27, its role in the regulation of T-cell proliferation must be con-sidered. A common finding of initial studies was that absence of the IL-27 receptor led to increased CD4+ T-cell proliferation following in vitro stimulation40,41. Paradoxically, IL-27 can enhance the clonal expan-sion of CD4+ T cells, but this effect is most apparent in the absence of the dominant T-cell growth factor IL-2 REFS 27,89. An explanation for the need to remove endogenous IL-2 to see the stimulatory effects of IL-27 is provided by the observation that IL-2 is a negative regulator of IL-27-receptor expression108. In addition, the finding that IL-27 has a marked suppressive effect on CD4+ T-cell production of IL-2 (A. Villarino and C.A.H., unpublished observations) largely explains the high levels of IL-2 that are observed in the absence of the IL-27 receptor (FIG. 4). However, it is important to acknowledge that IL-27 is likely to have additional inhibitory effects on T cells. Nevertheless, given the crucial role of IL-2 as a growth factor for T cells and its role in the development of TH1 and TH2 cells109, this observation provides the first insight into an inhibitory effect of IL-27 that helps to explain its broad suppressive effects on T-cell responses in several models.

Figure 4 | Interleukin-27 regulates the intensity and duration of T-helper-1 cell and T-helper-2 cell responses. Under conditions that polarize CD4+ T cells towards either T helper 1 (TH1) or TH2 cells — that is, in the presence of high levels of interferon-γ or interleukin-4 (IL-4), respectively — the production of IL-2 is an important first step in T-cell activation and contributes to the success and magnitude of either response. Naive CD4+ T cells express low levels of the IL-27-receptor subunit WSX1, but following activation under conditions that polarize them towards TH1 or TH2 cells, they produce high levels of IL-2 before the upregulation of WSX1 expression. However, as they become sensitive to IL-27, this cytokine antagonizes the sustained production of IL-2, which might explain, in part, the ability of IL-27 to inhibit TH1- and TH2-cell responses.


R E V I E W S


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

Effect of IL-27 on other haematopoietic cells. Although there has been a focus on the effects of IL-27 on CD4+ T cells, the expression of the IL-27 receptor by other haemato poietic-cell lineages indicates that this receptor–ligand interaction influences other immune cells. Although CD4+CD25+ regulatory T cells and memory T cells express the IL-27 receptor107, there are no published studies that have identified a biological effect of IL-27 on these T-cell subsets. Resting NK and NKT cells also express high levels of the IL-27 receptor107, and NK1.1+ cells from conA-challenged or T. cruzi-infected, IL-27-receptor-deficient mice produce more IL-4, IFN-γ and TNF than do wild-type mice. Similarly, macrophages and mast cells also express the IL-27 receptor, and in its absence, there is increased activation and production of inflammatory cytokines by these cells101,102,105. Together, these data indicate that IL-27 can suppress effector functions of a range of immune-cell types. Nonetheless, the mecha-nistic basis for these anti-inflammatory activities remains to be explored.

ConclusionsSince the description of IL-23 and IL-27 and their early association with TH1-cell responses, several studies have fundamentally changed how we view the immuno biology of these cytokines and have high-lighted the gaps in our understanding of how they function. Experimental models have had a prominent role in identifying the IL-23–IL-17 pathway and in associating these factors with the development of auto-immunity. Given that the levels of IL-23p19 and IL-17 are increased in human diseases such as multiple scle-rosis, Crohn’s disease, psoriasis, ulcerative colitis, cystic fibrosis, asthma, chronic obstructive pulmonary dis-ease and rheumatoid arthritis85,110–116, it is probable that events similar to those observed for mouse models are relevant to humans. So, on the basis of what we know about IL-23 and IL-17, it seems probable that they are viable targets for the treatment of these inflammatory conditions. This is illustrated by a Phase 2 clinical trial in which administration of an IL-12p40-specific human monoclonal antibody resulted in reduced clinical disease, and this was associated with improved histology of mucosal tissues and decreased production of cytokines by mononuclear cells that were isolated from the lamina propria117. But, as noted by the authors of this study, it is not clear whether the therapeutic effects of this treatment result from neutralization of IL-12 or IL-23.

One concern about the use of immunomodula-tors is that such approaches might leave patients immunocompromised. For example, TNF blockade as a treatment for rheumatoid arthritis can leave indi-viduals susceptible to a variety of opportunistic infec-tions118. However, although the use of antagonists of IL-12p40 in a clinical situation is in its infancy, early studies have not identified any marked side-effects117. Nevertheless, the loss of the IL-12–IFN-γ pathway in humans is associated with increased susceptibility to viruses, as well as Mycobacterium spp. and Salmonella

spp.39 Therefore, antagonists of IL-23p19 are viable candidates to ameliorate inflammation while leaving the IL-12–IFN-γ axis intact, and they might be less likely to compromise immunity to these opportunistic pathogens. Conversely, it seems unlikely that the main physiological function of IL-23 is to promote auto-immunity, and several studies have implicated a role for IL-23 in resistance to infection with certain pathogens. However, because IL-12 has a more restricted role in resistance to infection with opportunistic pathogens in humans than in mice, extrapolation of these find-ings to clinical situations must be carried out with care. It will probably be necessary to carry out appropriate trials of specific antagonists of IL-23 or to identify patients with unique defects in IL-23-mediated signal-ling (and to characterize their respective phenotypes) before we can define the contribution of IL-23 to the human immune system and determine whether it is a viable therapeutic target.

The use of parasitic systems to investigate the func-tion of IL-27 has provided unexpected insights into the biology of this interleukin. Whereas initial obser-vations from studies with L. major indicated a role for IL-27 in the promotion of TH1-cell responses, initial reports of studies with T. gondii, T. cruzi and T. muris have highlighted the suppressive effects of this cyto-kine. As more studies are carried out using different experimental systems, a better understanding should emerge of the circumstances in which the stimulatory or inhibitory effects of IL-27 dominate. This should help with the interpretation of reports that increased expression of IL-27 and its receptor are associated with chronic inflammatory conditions such as SARCOIDOSIS and Crohn’s disease119,120. At present, it is difficult to predict whether this indicates a pro-inflammatory role for IL-27 or points to an endogenous regulatory mechanism to limit T-cell activity. This knowledge could lead to strategies in which blockade of IL-27 might be useful for augmenting vaccine-induced immunity or to circumstances in which treatment with IL-27 could suppress inappropriate immune responses during autoimmunity or infection.

Although the focus of this Review article has been IL-23 and IL-27, there are several broad implications of the studies that have been discussed. It is important to remember that cytokines are pleiotropic, possessing the capacity to influence many elements of the immune system. So, although the pro- and anti-inflammatory effects of IL-27 might seem paradoxical, many other cytokines can show a similar dichotomy. So, IL-2, IL-6, TNF and the IFNs have well-characterized pro-inflammatory activities, but they also have suppressive effects121–128. Similarly, IL-10, one of the most potent inhibitors of cell-mediated immune responses can also provide stimulatory signals for B-cell growth129 and NK-cell production of IFN-γ129,130. Nevertheless, the basis for the suppressive effects of these cyto-kines remains obscure, and an important challenge is to understand the molecular events that determine whether the outcome of these cytokine–receptor interactions is a pro- or anti-inflammatory signal.




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AcknowledgementsI 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 unpub-lished data in this area of research. C.A.H. is supported by a grant from the National Institutes of Health (USA).

Competing interests statementThe author declares competing financial interests: see web version for details.

Online links

DATABASESThe following terms in this article are linked online to:Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geneEBI3 | gp130 | IL-6 | IL-6Rα | IL-12p35 | IL-12p40 | IL-12Rβ1 | IL-12Rβ2 | IL-17A | IL-17F | IL-23p19 | IL-23R | IL-27p28 | WSX1 Access to this interactive links box is free online.



new il-12-family members: il-23 and il-27, cytokines with divergent functions

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