Class II cytokine receptors and their ligands: Key antiviral and inflammatory modulators

© 2003 Nature Publishing Group

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NATURE REVIEWS | IMMUNOLOGY VOLUME 3 | AUGUST 2003 | 667

Interferons (IFNs) are arguably the oldest knowncytokines, first described in 1957 by Isaacs andLindenmann1, who reported that influenza-virusinfected chick-embryo cells secrete a protein that con-fers resistance to infection with influenza virus andother viruses. For many years, IFNs were thought tofunction only as inhibitors of viral replication, but laterwere shown to have pleiotropic effects. In particular,this is the case for IFN-γ, which has been shown to be a more potent pro-inflammatory than antiviralcytokine2,3. IFNs exert their activities through het-erodimeric receptors composed of transmembraneproteins that belong to the class II cytokine receptorfamily4. Interestingly, both chains that form the inter-leukin-10 receptor (IL-10R) complex were also foundto belong to this family of receptors5. IL-10 is a potentanti-inflammatory cytokine, originally described as afactor that inhibits the production of IFN-γ by mouse Tcells6. Although the homology between the primarysequences of IL-10 and IFNs is quite limited, the eluci-dation of their three-dimensional structure indicated ashared α-helical pattern, confirming that these factorsare structurally related7.

New members of this emerging family of ligands andreceptors have been identified by three experimental

approaches8–10. First, the discovery of several viral prod-ucts, which were homologous to either the IFN recep-tors or IL-10, indirectly showed the crucial role of theirmammalian homologues in antiviral defences. Second,new mammalian genes that encode IL-10-related fac-tors were described as the result of experiments usingCDNA SUBTRACTION CLONING focusing on melanocyte differ-entiation (IL24)11, virus-induced T-cell transformation(IL26)12 or IL-9-mediated gene induction (IL22)13.Finally, the sequencing and annotation of the humangenome led to the identification of five additional IFN-or IL-10-related genes14−17: IL19, IL20, IL28A (alsoknown as IFNλ2), IL28B (also known as IFNλ1) andIL29 (also known as IFNλ3). It is probable that all themembers of the family have now been described, and itis time to review the structural and biological infor-mation available about this family of cytokines, whichincludes potential new players in inflammatory pro-cesses. The main challenge ahead is to generate ameaningful picture that highlights the biological rele-vance of this highly complex network of molecules,combining our knowledge of older factors that werestudied extensively and our educated guesses aboutmore recently described molecules, some of which arestill orphan cytokines.

CLASS II CYTOKINE RECEPTORS ANDTHEIR LIGANDS: KEY ANTIVIRALAND INFLAMMATORY MODULATORSJean-Christophe Renauld

Class II cytokine receptors were originally defined on the basis of sequence homologies in theextracellular domains of receptors for interferons (IFNs) and interleukin-10 (IL-10), and the ligands,known as class II cytokines, also have a common structure. More recently, a series of newreceptors and cytokines that belong to this family have been discovered. The therapeutic potentialof the ‘old’ members of this family, IFNs and IL-10, is recognized in the clinic, and the existence ofstructurally related molecules is raising expectations for additional clinical applications. In this review,I discuss both structural and biological data that are emerging about this family of receptors andligands, to highlight the potential applications of modulating the activity of these cytokines.

Ludwig Institute for CancerResearch, Brussels branch,and Experimental MedicineUnit, Université de Louvain,74 Avenue Hippocrate,B1200 Brussels, Belgium.e-mail: [email protected]:10.1038/nri1153

CDNA SUBTRACTION CLONING

A method of cDNA cloningaimed to identify genes that areexpressed specifically in a giventissue or after a particularstimulation.


FIBRONECTIN DOMAINS

Fibronectin is an extracellularmultiadhesive protein that bindsto other matrix components,fibrin and cell-surface receptorsof the integrin family.Fibronectin is composed ofthree types of repeating amino-acid sequences. The type IIIfibronectin domain is a 100amino acid repeated domainthat is involved in the binding of integrins.

668 | AUGUST 2003 | VOLUME 3 www.nature.com/reviews/immunol

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more recent gene-duplication event leading to subsets ofgenes in the family — for example, type I IFNs, theIL28A−IL28B−IL29 subset and the IL19−IL20−IL24 sub-set (FIG. 1). However, genomic clustering does not per-fectly match the phylogenetic tree as illustrated by IFNγand IL22, which are only remotely homologous, but co-localize on chromosome 12q15. Although the family iswell conserved between humans and mice, some differ-ences have been described, especially for type I IFNgenes, which have probably evolved under the pressureof species-specific viruses. For example, the number ofgenes that encode IFN-α differs markedly betweenspecies; the mouse genome contains 14 functional IFNαgenes (Van Pesch et al., unpublished observations), threeIFN-α pseudogenes and one additional type I IFNgene, known as Limitin, which shows only 32% amino-acid identity with IFN-α18. The mouse genome alsoapparently contains no equivalent to human IL26.

In contrast to the modest amino-acid sequencehomologies — that is, no more than 15−25 % amino-acid identity between IL-10 and the other familymembers — three-dimensional structures indicated acommon structural theme based on six α-helices(referred to as helices A to F). However, the orientationof these helices allows two groups of cytokines to bedefined. On the one hand, IL-19, IL-22 and IFN-β arecomposed of six helices in an anti-parallel conforma-tion, resulting in monomeric bundle-like proteins19−21

(FIG. 2a). On the other hand, in IL-10 and IFN-γ struc-tures, the last two helices form a 90−120° angle with thefirst four helices, forming V-shaped molecules that asso-ciate as homodimers, in which helices E to F from onepartner intercalate between helices A to D from theother partner22,23 (FIG. 2b).

In parallel with these structurally related ligands, afamily of receptors known as class II cytokine receptorswere described on the basis of the structure of their extra-cellular domain. This family is defined by the presence intheir extracellular domain of two type III FIBRONECTIN

DOMAINS, but are distinguished from haematopoieticreceptors or class I cytokine receptors by the differentposition of the conserved cysteine sequence and by theabsence of a Trp-Ser-Xaa-Trp-Ser motif 7,24. Thecytokine-binding site is located at the interface betweenthese two domains, through five loops from the two β-sheets of the receptor7,25 (FIG. 2c). Noticeably, the simi-larities between these cytokine receptors are limited tothe extracellular ligand-binding domain and do notextend to the cytoplasmic domain.

There are 12 members of the class II cytokinereceptor family (FIG. 1B). Ten of them consist of classictransmembrane proteins that heterodimerize to formhigh-affinity binding sites for class II cytokines. Thesecan be roughly classified as either long- or short-chain receptors, on the basis of the length of theircytoplasmic domain. Functional receptor complexesconsist of heterodimers, usually involving one long-chain and one short-chain receptor. Many of thesechains are involved in more than one receptor com-plex. For example, the IL-10Rβ chain associates withIL-10Rα to bind IL-10 (REF. 26), with IL-22R to bind

Structural characteristicsFrom an evolutionary point of view, the genomic orga-nization and structural characteristics of the class IIcytokines indicate that they, despite their relatively weakprimary sequence similarities, derive from a commonancestor. Genes that encode these proteins are clusteredon four different loci of the human or mouse genomes.In humans, genes encoding type I IFNs include 13 func-tional intron-less non-allelic genes that encode IFN-αand a single copy of IFN-β and IFN-ω, which all co-localize to chromosome 9p22. The gene encoding IFN-γ(also known as type II IFN) is located on human chro-mosome 12q15, together with the IL22 and IL26 genes.The IL10 gene is located on chromosome 1q32, togetherwith the IL19, IL20 and IL24 genes, and the genes encod-ing IL-28A, IL-28B and IL-29 co-localize on chromo-some 19q13. A phylogenetic tree based on amino-acidsequences indicates that some of these loci underwent a

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IL-10R2IFN-αR1-nIFN-γR2IFN-γR1IFN-αR1-cIFN-αR2

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Figure 1 | Phylogenetic tree of class II cytokines andreceptors. The sequences of the human class II cytokines (a)and the extracellular domain of their receptors (b) werealigned using the ClustalW multiple alignment software (seefurther information for website). As the classical class IIcytokine-binding domain is duplicated in the interferon-αreceptor 1 (IFN-αR1) chain, the sequence of this receptor hasbeen split into IFN-αR1-n (amino) and IFN-αR1-c (carboxyl)for the first and second cytokine-receptor domains,respectively. The genomic localization of the correspondinggene in humans and the amino-acid identity with interleukin-10(IL-10) for the cytokines, and with the extracellular domain ofIL-10 receptor (IL-10R) are also indicated. The percentage ofamino-acid identity was determined using the Lipman and Pearson’s align programme (see further information for website). BP, binding protein; IL-TIF, IL-10-related T-cell-derived inducible factor; MDA7, melanocytedifferentiation antigen 7; TF, tissue factor.



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functions as a receptor for coagulation factor VIIa.Although the extracellular domain of this proteinretained the structural characteristics of a cytokinereceptor, it seems to have lost its cytokine-bindingfunction during evolution31. IL-22BP has a typicalclass II cytokine-binding domain, but no potentialtransmembrane and cytoplasmic domain, indicatingthat it is a soluble receptor. Indeed, IL-22BP is asecreted protein that specifically binds IL-22 andseems to function as an IL-22 antagonist in vitro32−35.In vivo, this soluble receptor might act as either acytokine carrier molecule or a cytokine antagonist.Such natural antagonists or decoy receptors weredescribed in other cytokine families, including IL-18BP and osteoprotegerin, and probably allow forphysiological modulation of the activity of potentiallyharmful factors36.

IL-22 (REFS 27−29), with IL-28R to bind IL-28 or IL-29(REFS 16,17) and with an unknown chain to form theIL-26R complex (L. Dumoutier and J.-C. R., unpub-lished observations). In addition, a high level of com-plexity in these cytokine−receptor interactions resultsfrom the fact that one particular cytokine can bind totwo different receptor complexes, and that one partic-ular receptor complex can bind several cytokines,potentially transducing distinct signals, as indicatedfor type I IFNs, that might have partly different activi-ties through a single receptor30. The interactionsdescribed in the family are schematically representedin FIG. 3.

Two members of this family, however, show distinctcharacteristics: tissue factor and IL-22 binding protein(IL-22BP). Tissue factor is a transmembrane receptorthat apparently does not bind to any cytokine, but

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Figure 2 | Three-dimensional structure of monomeric and dimeric class II cytokines. a | Comparison of the three-dimensional structures of human interferon-β (IFN-β), interleukin-19 (IL-19) and IL-22. The proteins are coloured starting from theamino-terminus in blue and ending with the carboxyl-terminus in red. At the far right of the figure, a model is represented for thesethree proteins, viewed from the top, with the six α-helices labelled and coloured as in the actual structures. b | The structure of an IL-10 monomer is represented from a similar angle and with the same colour code as its paralogues in (a). The organization of thesix helices in an IL-10 monomer and dimer is shown schematically to the right. c | The structure of an IL-10 monomer (blue) inassociation with the extracellular domain of the IL-10 receptor α (IL-10Rα) chain (green).



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virus (EMCV) or after stimulation with poly I:C,indicating that the type I IFNs and the IL-28−IL-29 sub-family have common regulatory elements16,17.Interestingly, the sequences of these two subfamilies areonly remotely related. IL-29, for example, has no morethan 17% amino-acid identity with IFN-α. Theirgenomic structures also differ from the intron-less type IIFN genes, as the IL28 and IL29 genes contain five exons.Finally, their respective receptor complexes have nocommon chains that would explain overlapping activi-ties16,17. However, IL-28 and IL-29 seem to have biologi-cal effects that are similar to type I IFNs. Activation ofSTAT2 is a common feature of these cytokines, whichwas, until now, considered to be a relatively specificcharacteristic of the type I IFN response38. More impor-tantly, IL-28 and IL-29 were reported to protect humancell lines against the cytopathogenic effect of EMCV orvesicular stomatitis virus (VSV)16,17, indicating a potentantiviral activity and supporting the proposal byKotenko and colleagues17 to rename these factors asIFN-λ1, IFN-λ2 and IFN-λ3.

The relative roles of type I IFNs and IL-28/IL-29 inantiviral responses remain to be established. Studies in mice that are deficient in either subunit of the type IIFNR complex point to an essential role for this receptorand its ligands in resistance to certain viruses39. How-ever, infection by some viruses, such as rotavirus, wasnot modified in type I IFNR-deficient mice, raising thepossibility that each subfamily of antiviral factors targetsa distinct subset of viruses2,38,39. Alternatively, differentexpression patterns of the respective receptor chainscould result in tissue-specific antiviral activity for thesecytokines. In this respect, the expression of the type IIFNR chains is considered to be ubiquitous, whereas the expression of IL-28R might be more variable in dif-ferent tissues16,40. Although it remains to be formallyshown, the hypothesis that IL-28/IL-29 are functionallyequivalent to type I IFNs but act on a more restrictednumber of cell types might have important therapeuticconsequences. Type I IFNs have been approved for use in many clinical situations, including, but notrestricted to, viral infections. However, treatment withIFN leads to significant side effects such as fatigue, fever,anorexia, depression and myelosuppression. With amore restricted panel of target cell types, IL-28/IL-29would be expected to recapitulate at least some of thebeneficial activities of IFN in vivo, but maybe with lessadverse side effects.

IFN-γ has a weaker direct antiviral activity in vitro, anddoes not activate the same pattern of STAT2-dependentantiviral genes as type I IFN or IL-28/IL-29. However,IFN-γ is also produced by T cells and natural killer (NK)cells during many viral infections. An IFN-γ-deficientresponse is associated with increased susceptibility tomycobacteria infection rather than to viral infections,but IFN-γ and its receptor are required for resistance tosome viruses, such as mouse hepatitis virus (MHV)41,42.

The crucial role of class II cytokines and receptorsduring infection with viruses is best illustrated by the factthat many viruses have captured and subverted genesfrom this family, presumably to neutralize the host

The crucial components in class II cytokine sig-nalling are signal transducers and activators of tran-scription (STATs) and Janus tyrosine kinases (JAKs)4. Allreceptor chains are associated with a member the JAKfamily, which becomes activated when the ligand bindsthe corresponding heterodimeric receptor. This leads tophosphorylation of the receptors, which creates dock-ing sites for STAT factors. These transcription factorscan then be phosphorylated by the JAKs, form dimersthrough their SRC homology 2 (SH2) domain andmigrate to the nucleus where they activate the transcrip-tion of a series of target genes. All these receptors acti-vate STAT3 and STAT1, and some of them also activateSTAT2, which is associated with antiviral activity, andSTAT5. Beside this common pathway, some of thesereceptors, such as the type I IFNR or the IL-22R, havebeen shown to activate mitogen-activated protein kinase(MAPK) pathways — that is those involving the ERK,JNK and p38 kinases2,37 (FIG. 4).

Biological functionsDespite the structural similarities and the sharing ofcommon receptor chains, the physiological roles of class II cytokines seem to be divergent. The bestillustration of these different, and sometimes antago-nist, activities can be seen by comparison of IL-10 andIFN-γ. IFN-γ is a major pro-inflammatory cytokine,because of its ability to activate macrophages andendothelial cells2,3. By contrast, IL-10 downregulatesthe expression of activating and co-stimulatory mole-cules, as well as the production of pro-inflammatorycytokines by macrophages6. So, with regards to bio-logical functions, IL-10- and IFN-related cytokines donot form a homogeneous cytokine family. The struc-tural similarities reflect the use of a common type ofprotein interaction between the ligand and the extra-cellular domain of the receptor. Biological activitiesmainly depend on the cytoplasmic domains, whichtrigger overlapping sets of signalling cascades but showbasically no sequence similarity in the family, and on the pattern of expression of the receptor chains,which differs completely and, therefore, define a dis-tinct spectrum of target cells from one member toanother. However, several areas, in which class II cyto-kines are regularly observed to have important roles,deserve to be mentioned especially in the context ofpotential clinical applications. These include responsesagainst viral infections, inflammatory processes andantitumour activities.

Antiviral responses. Most animal viruses induce theexpression of type I IFNs from various cell types; IFN-αis preferentially expressed by cells of a lymphoid originand IFN-β is expressed by virtually all cell types2. It hasbeen postulated that double-stranded RNA (dsRNA)might be the common mechanism by which virusesinduce the expression of IFNs, and the synthetic polymerpoly I:C is the tool most widely used to induce these fac-tors. Recently, IL-28A, IL-28B and IL-29 were also shownto be expressed by human peripheral-blood mono-nuclear cells after infection with encephalomyocarditis



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cause a mild feverish illness when transmitted to humans.Interestingly, this protein showed only 23% amino-acididentity with human IL-10 and 27% identity with IL-24.Preliminary results indicate that this protein might notbind to the IL-10R but, similar to IL-20 and IL-24, bindsto both type I and type II IL-20R complexes (N. Bartlett et al., unpublished observations). The putative advantageconferred by binding of this viral protein to IL-20Rs isstill unclear, but is presumably more related to a kind ofautocrine loop, involving keratinocytes, than to a modu-lation of the antiviral response. Such an autocrine loophas also been indicated for B-cell transformation medi-ated by EBV. In this case, both virus-encoded andendogenous IL-10 are expressed after infection with virusand could contribute to B-cell proliferation through theB-cell growth-factor activity of IL-10 (REF. 57). Interest-ingly, herpes saimiri virus, which induces transformationof T cells, markedly upregulates the expression of IL-26,and it is tempting to speculate that IL-26 could have a rolein virus infection or T-cell transformation12.

Modulation of inflammatory processes. Inflammation isdefined as a complex response to local injury or othertrauma, resulting in redness, heat, swelling and pain.This involves a cascade of events that include cytokineproduction, cell trafficking, extravasation, mediator pro-duction, coagulation, fibrinolysis and changes in hemo-dynamic parameters and microvascular permeabilitythat can ultimately lead to death. Administration oflipopolysaccharide (LPS) is a classic experimental modelthat has been used widely to assess the role of cytokinesin systemic inflammation, implicating tumour necrosis

response43.A direct way for a virus to escape the antiviralresponse is to encode soluble IFNRs, which could com-pete with cell-surface receptors for binding of the ligand.For example, the vaccinia virus genome encodes a solubleclass II cytokine receptor that is specific for IFN-γ44,45, aswell as a gene from the immunoglobulin superfamilythat binds and neutralizes IFN-α/IFN-β 46,47.

As mentioned earlier, the production and activitiesof IFN-γ are often antagonized by IL-10, and IL-10might by this way indirectly favour viral infection.Sequencing of the mouse Il10 gene indicated that asimilar sequence, known as BCRF1, was present in thegenome of EPSTEIN−BARR VIRUS (EBV)48. This viral proteinhas 84% amino-acid identity with human IL-10, butseems to retain only a subset of IL-10 activities, mainlyanti-inflammatory effects49,50. The hypothesis that theexpression of virus-encoded IL-10 provides EBV withan evolutionary advantage, is supported by the fact thatthe genomes of several other viruses of the herpes-virusfamily contain genes with more than 80% identity toendogenous IL-10, including the baboon herpes viruspapio (HVP), the equine herpes virus type 2 (EHV2)51

and the ovine Orf parapoxvirus52. More distant IL-10homologues (25−30% amino-acid identity) have beendescribed in the genomes of human and simian cyto-megaloviruses (HCMV and SCMV)53,54. Despite its lim-ited similarity with human IL-10, CMV-encoded IL-10seems to have similar IL-10R-binding capacity53,55.

The last member of the virus-encoded IL-10-relatedfamily was discovered in the genome of the monkeyyatapoxvirus Yaba-like disease virus (YLDV)56 — a virusthat causes skin lesions in infected monkeys and might

EPSTEIN–BARR VIRUS

(EBV). A double-stranded DNAvirus of the herpes-virus family,which is the aetiologic agent ofinfectious mononucleosis and isassociated with some B-cellmalignant tumours andnasopharyngeal carcinoma. EBVinfects B cells and some epithelialcells by specifically binding tocomplement receptor 2 (CD21).

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Figure 3 | Schematic representation of the functional receptor complexes for class II cytokines. The ligands are shownabove their respective receptor complexes. The cytoplasmic domains of the receptors are shown in green, and the two fibronectintype III domains comprising the cytokine-binding domain are shown in orange and yellow. With the exceptions of interleukin-22binding protein (IL-22BP) and tissue factor (TF), receptor complexes are formed by two chains, one chain with a relatively shortcytoplasmic domain (for example, IL-10 receptor β (IL-10Rβ) and one chain with a longer cytoplasmic domain (for example, IL-10Rα).The characteristics of this family is that one chain is involved in several receptor complexes, that one ligand can bind several differentcomplexes and that several ligands can bind to the same complex of receptors.



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lymphoid cells would indicate a pro-inflammatoryfunction, but in vivo anti-inflammatory activity hasbeen shown in patients with multiple sclerosis, in whichIFN-β reduces the frequency of IFN-γ-secreting cells, aswell as the frequency of relapses63.

T helper (TH

) cells have a crucial role in the regu-lation of inflammatory responses and can be classifiedinto two main functional subsets on the basis of thespectrum of cytokines that they produce64. T

H1 cells

produce IFN-γ and TNF-β, and are responsible formany cell-mediated immune responses, in which IFN-γ has a key role. They are also associated with thepromotion of excessive inflammation and tissue injury.T

H2 cells produce IL-4, IL-5, IL-9, IL-10 and

IL-13, and are involved in immunity against extracellu-lar pathogens and in allergic reactions65. Originally,IL-10 was described as a T

H2-promoting cytokine,

because it was discovered as a factor that inhibits theproduction of IFN-γ by mouse T

H1 cells66. Later, the

ability of IL-10 to inhibit cytokine production by T cells was shown to be mainly indirect, through theinhibition of accessory cells, and reflects the anti-inflammatory effect of IL-10 on activated macrophages67.More recently, CD4+ regulatory T-cell populations thatproduce high levels of IL-10 have been described, andwere indicated to have an essential role in tolerance toself-antigens68. The relative contribution of IL-10 in thefunction of such regulatory T cells varies depending onthe experimental model, but its anti-inflammatory activ-ity corresponds to the immunosuppressive function ofthese cell populations69.

factor (TNF) and IL-1 as crucial pro-inflammatory fac-tors for the initiation and propagation of inflammatoryprocesses. By inhibiting the production of these factors,IL-10 exerts a potent anti-inflammatory activity, which isillustrated in vivo by the fact that administration of IL-10rescued mice from LPS-induced toxic shock58,59. In addi-tion, endogenous IL-10 is induced by LPS and confersprotection from the harmful effects of endotoxin chal-lenge, as blocking IL-10 markedly increased the sensitiv-ity of mice to LPS60. This effect seems to be specific forIL-10 and could not be reproduced with any of the otherIL-10-related cytokines.

The expression of IFNs is also upregulated byinflammatory stimuli, such as LPS, and their pro-inflammatory roles have been shown in many differentmodels. IFN-γ is a potent activator of the macrophage/monocyte lineage, and blocking IFN-γ increases theresistance to endotoxin challenge61. Interestingly, inhi-bition of IFN-γ also suppressed the inflammation of theintestine that characterizes IL-10-deficient mice, fur-ther illustrating the fact that IL-10 and IFN-γ are antag-onistic cytokines and that a balance in the productionof these factors is required to maintain the homeostasisof inflammatory processes62. As inflammation can beconsidered to be one of the first steps of an efficientimmune response, it is not surprising that so manyviruses encode IL-10-related or soluble IFN-γ receptor-like genes that might contribute to downregulate thehost response to the viral infection. The actual role oftype I IFNs in inflammation is more complex. The in vitro effects of IFNα/IFNβ on monocytes and

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Figure 4 | Schematic representation of signalling pathways activated by class II cytokine receptors. High-affinity bindingrequires the association of two class II cytokine receptor chains. After ligand binding, the receptor-associated Janus-family tyrosinekinases (JAKs) become activated by auto- or cross-phosphorylation and phosphorylate the cytoplasmic domain of the receptor.Depending on the receptors, these phosphorylated tyrosine residues function as docking sites for cytoplasmic adaptors that triggerthe different mitogen-activated protein kinase (MAPK) pathways, ERK (extracellular signal-related kinase), JNK (JUN N-terminalkinase) and p38 — for example, activation through type I interferon receptor (IFNR) and by cytokines that bind to interleukin-22receptor (IL-22R) — or for signal transducer and activator of transcription (STAT) factors. After recruitment to the receptor, STATsbecome phosphorylated, form homo- or heterodimers and migrate to the nucleus to bind to specific sequences in the promoter oftarget genes. STAT1 and STAT3 are activated, to various extents, by all class II cytokine receptors and bind to consensussequences known as GAS (IFN-γ activated sites). Type I IFNR chains and IL-28R also activate STAT2, which then associates withSTAT1 and IFN regulatory factor 9 (IRF9), migrates to the nucleus and binds to IFN-stimulated response elements (ISREs), which areresponsible for the induction of a series of antiviral genes.



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do not have the same phenotype as mice transgenicfor IL-20 (REF. 78). As IL-19 binds to IL-20R type 1, butnot IL-20R type 2 complexes, it is probable that thelatter receptor complex, composed of IL-22R and IL-20Rβ, is responsible for the skin phenotype. Finally,IL-22-transgenic mice are also non viable and, althoughdetailed description of these mice is limited, apparentskin abnormalities further support the role of IL-22Rin the regulation of keratinocyte differentiation andproliferation.

Anticancer activities. Type I IFNs are potent negativeregulators of cell growth, either by modulating the cellcycle or by inducing pro-apoptotic genes2. The therapeu-tic efficacy of IFN-α was first shown for hairy-cellleukaemias and Kaposi’s sarcoma, and subsequent stud-ies indicated its activity against chronic myelogenousleukaemia, B- and T-cell lymphomas, melanoma, multi-ple myelomas and renal-cell carcinoma80. The recentfinding that IL-28 and IL-29 share many type I IFNactivities16,17 indicates that these new cytokines mighthave similar effects. In vitro, IL-29 has a potent growthinhibitory activity on mouse lymphoma cells thatexpress IL-28R (L. Dumoutier and J.-C. R, unpublishedobservations), but fails to inhibit the proliferation of theDaudi EBV-transformed human cell line16, which isoften used as the classic assay for the growth-inhibitoryeffect of IFNs. Taken together, these observations indi-cate that IL-28 and IL-29 might indeed have antitumouractivity, but the spectrum of target cells might be differentfrom IFN-sensitive cell types.

IL-24 was originally described as a gene the expres-sion of which was upregulated after human melanomacells were treated with IFN-β plus the protein kinase Cactivator mezerein — a treatment that induces a revers-ible loss in growth potential, suppression of tumouri-genic potential and terminal differentiation11. IL-24,which was therefore initially known as melanocyte dif-ferentiation antigen 7 (MDA7), is expressed by normalmelanocytes and its expression decreases progressivelyduring the process of melanoma transformation andprogression to metastatic melanoma81,82. The gradualloss of expression observed with melanoma progressionsupports the possibility that IL-24 might have a role intumour suppression, at least in this cell type. In order totest this hypothesis, Fisher and colleagues83 constructedIL-24-encoding adenovirus vectors for the ectopicexpression of IL-24 by human melanoma cells. Suchrecombinant adenoviruses induced growth suppressionwithout the induction of terminal differentiation, andthis observation was extended to a broad spectrum ofhuman cancers, but not to normal cell types. This wasalso observed in animal xenograft models, providing arationale for phase I and II clinical trials that are inprogress at present84.

In breast-cancer cell lines, infection with the IL-24-encoding adenovirus induced signs of apoptosis, whichcorrelated with an upregulation of expression of thepro-apoptotic protein BCL-2-associated X protein (BAX)and changes in the ratio of BAX to BCL-2 (REF. 85). Inaddition, co-expression of BCL-2 inhibited the activity

The role of the other IL-10-related cytokines duringinflammation is more elusive. Interestingly, activated T

H1

cells, but not TH2 cells or regulatory T cells, secrete IL-22

(REF. 70). By contrast, IL-24 seems to be preferentially pro-duced by T

H2 cells, at least in mice71. Most of these fac-

tors (IL-19, IL-20, IL-22 and IL-24) have also beenshown to be inducible by LPS14,28,70. However, the IL-20Rα and IL-22R chains do not seem to be expressedby immune cells, including monocytes, NK cells, B and T cells and bone-marrow cells70, and none of these factorsseems to have anti-inflammatory activity. In contrast toIL-10 and IFN-γ, which mainly act on monocytes/macrophages, these cytokines do not seem to modulatethe activation of inflammatory cells directly, althoughIL-19 and IL-24 were reported to upregulate the production of IL-6 by mononuclear cells72,73.

IL-22 was reported to downregulate the production of IL-4 by T cells29, however this T

H2-modulating activ-

ity has not been confirmed and T cells do not seem toexpress IL-22R. By contrast, liver cells respond to IL-22 byupregulating the expression of ACUTE-PHASE REACTANTS

(APRs)28. The induction of APRs is not a unique charac-teristic of IL-22, and other inflammatory cytokines,such as IL-1, TNF and IL-6, which are released in largeamounts during inflammation, probably have a moreprominent role in this process74,75. Indeed, IL-22 doesnot seem to be required for the production of APRs inresponse to LPS (L. Dumoutier and J.-C. R, unpub-lished observations). However, this effect of IL-22 mightbe more important in particular conditions where IL-22is produced preferentially. In addition, the production ofAPRs is not restricted to the liver, and IL-22 also inducedhigh levels of expression of APRs in other organs, such aspancreas76. It is, therefore, possible that the extent ofcytokine redundancy varies between organs and IL-22might be required for local APR induction in organsthat express high levels of IL-22R, such as the pancreas,lungs and gut.

In this respect, several observations point to the skinas a potential main target for the pro-inflammatoryactivity of IL-22, and also IL-19, IL-20 and IL-24.The skin has a high level of expression of the differentchains that compose their respective receptor com-plexes: IL-22R and IL-10Rβ for IL-22 (REFS 27,29);IL-20Rα and IL-20Rβ for the IL-20R type 1, whichbinds IL-19, IL-20 and IL-24 (REFS 77−79); and IL-22Rand IL-20Rβ for the IL-20R type 2, which binds IL-20and IL-24 (REFS 77−79). The phenotype of mice that con-stitutively express IL-20 confirmed the effect of thiscytokine on the skin. Such constitutive expression ofIL-20 is lethal within a few days after birth. Histologicalanalysis indicated a markedly thickened epidermis char-acterized by increased numbers of keratinocytes andexpression by the suprabasal layers of differentiationand proliferation markers that are normally confinedto the basal layer15. This observation is reminiscent ofthat which occurs in the skin of patients with PSORIASIS.Because expression of IL-20Rα and IL-20Rβ (IL-20Rtype 1) was found to be upregulated in the skin ofpatients with psoriasis, it was proposed that IL-20might have a role in this disease. IL-19-transgenic mice

ACUTE-PHASE REACTANTS

(APRs). APRs consist of plasmaproteins the expression of whichis up- or downregulated duringinflammation as the result of theendocrine activity of cytokines.Most APRs are produced by theliver and include components ofthe complement pathways,factors of the coagulationsystem, proteinase inhibitors,metal-binding proteins andother proteins involved invarious infection-associatedfunctions.

PSORIASIS

A chronic skin disease thataffects 1–2% of the population,in which the skin becomesinflamed, producing red,thickened areas with silveryscales, most often on the scalp,elbows, knees and lower back.Recent evidence points to a T-cell-mediated pathogenesis ingenetically susceptibleindividuals, resulting ininflammation and epidermalhyperplasia.



R E V I E W S

of RNA-DEPENDENT PROTEIN KINASE (PKR) has also beenreported to correlate with IL-24-induced apoptosis89

and might also have a role in this process, but it is notknown whether this effect depends on the delivery ofadenovirus or can be reproduced with the recombinantsoluble protein.

The correlation of expression of IL-24 with differen-tiation has, so far, only been shown in the context ofmelanoma. Other cell types do not express IL-24, exceptfor activated monocytes and lymphocytes70,90. Thismight indicate distinct roles for this gene depending onthe tissue: a growth regulating role in melanocytes and arole in inflammatory responses for immune-cell-derivedIL-24. In this regard, IL-24 was reported to upregulatethe production of IL-1, IFN-γ and TNF by humanperipheral-blood mononuclear cells73, although thisneeds to be confirmed as it contrasts with the expressionpattern of IL-20Rα and IL-22R, which are required forIL-24 responsiveness70,77.

Conclusion and perspectivesThe family of class II cytokine receptors and their ligandsare grouped together on the basis of structural homolo-gies, indicating that these genes derive from commonancestors. Interestingly, the fact that extracellulardomains of these receptors share 20−30% amino-acididentity indicates that the duplications of these genesoccurred during a relatively short period of evolution,and might have been selected in response to environ-mental challenges. From all the functional data that havebeen summarized earlier, it seems that these cytokinesand receptors mediate heterogeneous and sometimesantagonistic activities, but essentially are involved in theregulation of inflammatory and antiviral responses. Inthis respect, it must be stressed that gene-targeting exper-iments have shown that neither type 1 and type 2 IFNs,nor the factors that use the IL-10Rβ chain (IL-10, IL-22,IL-26, IL-28 and IL-29) seem to have a role in embryoge-nesis or in the ontogeny of any tissue. All knockout micedescribed for this family remain viable and healthy.A phenotype occurs in these animals only in the pres-ence of viruses or bacteria, either resulting from uncon-trolled dissemination of the infectious agent or from aninappropriate inflammatory response to these stimuli.

The main question that remains is whether ourunderstanding of the biology of the most recently iden-tified class II cytokines will open the way to new thera-peutic possibilities. In this respect, at least three excitingavenues of research have been unravelled. The puzzlingtumour-specific cytotoxicity of adenovirus delivery ofIL-24 requires that both the efficacy and the mecha-nisms of this new antitumour strategy are further inves-tigated. The finding that new molecules, such as IL-28and IL-29, partly reproduce the activities of type I IFNshave obvious potential applications in antiviral andantitumour therapy. Finally, the potent effects of IL-20and IL-22 on keratinocytes and skin inflammation pro-vide us with new tools to treat skin inflammatory dis-eases. To collect these tools is an important step, tolearn how to use them and to what purpose is the nextchallenge that we are facing.

of IL-24, corresponding to a potential BAX-mediatedeffect85. However, the IL-24-encoding adenovirus alsoinduced an effect in cells that lack a functional BAXgene, indicating BAX-independent modes of actionaswell84. Growth arrest and DNA-damage-inducible(GADD) proteins might have a role in this process.GADD proteins comprise a family of five nuclear pro-teins, GADD34, GADD45α, GADD45β, GADD45γ andGADD153, which are essentially stress-responsive mole-cules, and are associated with cell-growth arrest and/orapoptosis86. The expression of these proteins was upreg-ulated after infection of melanoma cells with IL-24-encoding adenovirus. Moreover, a selective p38 kinaseinhibitor inhibited this induction of expression, andprovided protection against IL-24-mediated cell death,supporting the hypothesis that IL-24 can induce apop-tosis through the induction of expression the GADDfamily proteins through the p38 kinase pathway87.

The upstream signalling events that underlie theanticancer effect of IL-24 remain poorly understood.Surprisingly, the spectrum of sensitive tumour-cell linesdoes not correlate with the expression of any of thereceptor complexes that bind IL-24 (REF. 84), and it is notyet clear whether recombinant IL-24 exerts an anti-tumour effect that is comparable to the adenovirusconstruct. Several hypotheses might explain why thedelivery of adenovirus seems to be required for thisactivity. This expression system could result in high localconcentration of the cytokine, resulting in activities thatare not observed with lower concentrations of therecombinant cytokine potentially through an as yetunknown receptor. Alternatively, adenovirus infectionmight induce the expression of the receptor chains thatare involved in the activity of IL-24, thereby enhancingthe effect of the cytokine. Finally, it is possible that IL-24can be produced either as a soluble or as a cytoplasmicisoform depending on the cell type. Activated T cells andmonocytes might mainly produce soluble IL-24 thatfunctions through its cell-surface receptor, whereas theantitumour effect described for non-haematopoietic cellsmight result from the cytoplasmic isoform only. Such acytoplasmic isoform could be produced by using analternative initiation codon in the 5′ region of the IL-24messenger RNA. In this respect, it should be stressedthat initial reports on IL-24 did not recognize this proteinas a secreted factor, probably because its amino-terminalsequence, starting from this first initiation codon, is notan optimal signal peptide sequence.

However, some observations support the involve-ment of a cytokine receptor mechanism. In a malignantglioma model, both recombinant IL-24 and the adeno-virus−IL-24 construct showed similar antitumour activ-ities in synergy with ionizing radiation88. In lung cancercells, the effect of the adenovirus construct correlatedwith phosphorylation of STAT1, STAT3 and tyrosinekinase 2 (TYK2) (REF. 89). Moreover, both the activationof p38 kinase and the induction of expression ofGADD45γ are observed after infection with IL-24-encoding adenovirus87 and after stimulation of IL-22through activation of the IL-22R37, which also binds IL-24 (REFS 77–79). Finally, the upregulation of expression

RNA-DEPENDENT PROTEIN

KINASE

(PKR). PKR is a protein kinasethat requires double-strandedRNA to exert its activity. This issupplied by virus RNA, whichfrequently loops back on itself toform double-stranded regions.One of the substrates of PKR istranslation initiation factor 2(IF2) — a factor involved inprotein synthesis. IF2 is essentialfor the initiation complex ofprotein synthesis, but loses itsactivity after phosphorylation.



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Online links

DATABASESThe following terms in this article are linked online to:LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/BAX | GADD34 | GADD45α | GADD45β | GADD45γ | GADD153 |IFN-α | IFN-β | IFN-γ | IFN-ω | IL-1 | IL-10 | IL-10R | IL19 | IL20 |IL22 | IL-22BP | IL24 | IL26 | IL28A | IL28B | IL29 | PKR | STAT1 |STAT2 | STAT3 | STAT5 | TNF | TYK2

FURTHER INFORMATIONClustalW multiple alignment programme:http://www.ebi.ac.uk/clustalw/index.htmlLipman and Pearson’s align programme:http://molbiol.soton.ac.uk/compute/align.htmlAccess to this interactive links box is free online.

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Class II cytokine receptors and their ligands: Key antiviral and inflammatory modulators