Michael R. Edwards

Parronchi P

Sebastian L. Johnston

EMBO Molecular Medicine

English

PubMed

Crossref

Interferon‐lambda as a new approach for treatment of allergic asthma?

Edwards, MR

Johnston, SL

Spiral - Imperial College Digital Repository

Interferon-lambda as a new approach fortreatment of allergic asthma?Michael R. Edwards, Sebastian L. Johnston*Keywords: allergy, asthma, interferon, mouse model, Th1/Th2See related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201100142Asthma is a heterogeneous inflammatorydisorder of the lung caused principally bysensitization and exposure to an allergen,but also influenced by environmentalfactors such as cigarette smoking, stress,exercise, pollution, respiratory virusinfection and certain respiratory bacteria.The cardinal features of asthma includewheeze, shortness of breath, variableand reversible airway obstruction, air-way hyperresponsiveness, mucus pro-duction and airway inflammation. Aller-gic asthma is the most common formof asthma, caused by sensitization andexposure via the airways to a number ofinnocuous allergens including proteinsfrom house dust mites, animals, mouldsand tree and grass pollens. Sensitizationand challenge elicits a response from Th2helper T cells and, through the actions ofinterleukin (IL)-4, IL-5 and IL-13, IgEproduction, airway eosinophilia, mastcell activation, mucus production andairway hyperreactivity ensues. Mildasthma can be well controlled by inhaledsteroid therapies or inhaled steroid-b2agonist combinations. However, in mod-erate to severe asthma, adequate controlfrequently cannot be achieved with thesetherapies, and new and better treatmentsare therefore required.Asthma exacerbations are acuteattacks of asthma when an otherwise‘stable’ asthmatic experiences a rapidincrease in symptoms accompanied bydecreased lung function, most oftenprecipitated by a respiratory virus infec-tion. Asthma exacerbations are respon-sible for the vast majority of the morbid-ity and mortality associated with asthma;and represent an area not well controlledby current therapy regimes. The searchfor new asthma therapies remains anintensive area of interest, and the last10 years have seen a number of noveltherapeutic strategies applied to bothstable asthma and asthma exacerbations,including new formulations of steroidsand b2 agonists, anti-Th2 cytokine thera-pies, anti-TNF-a therapies, etc.The work by Koltsida et al (Koltsidaet al, 2011) in this issue of EMBOMolecular Medicine is of outstandingimportance in this regard for two rea-sons. The current study clearly showsthat IL-28A, a newly designated type IIIinterferon (IFN)-l, an anti-viral cytokine,can ameliorate the allergic and Th17-induced inflammation that occurs aftersensitization and challenge with aero-solized allergen in mice, which closelyresembles that seen in allergic asthma inhumans. This data shows that IFN-lsmay have additional properties in addi-tion to their anti-viral capacity, such thatthey may be antagonists of Th2 and Th17responses and function by inducing theTh1 polarizing cytokines type II IFN-gand IL-12. The second noteworthy pointis that asthmatics have recently beenobserved to be deficient in type I IFN-band type III IFN-ls (Contoli et al, 2006;Wark et al, 2005), and a deficiency inIFN-ls may increase the severity of virus-induced asthma exacerbations (Contoliet al, 2006). Together, these studiespropose a dual importance of IFN-l thathad previously not been demonstrated.The IFN system is composed of threetypes of IFN: the anti-viral type I IFNs(the single IFN-b and the multiple IFN-as), the type II IFNs and the type III IFN-ls. Type II IFN-g is fundamentallydifferent, has different cell type-specificexpression patterns, is produced byleukocytes upon a number of stimuli, isnot strictly limited to virus infection, andhas numerous modes of action. Impor-tantly, type I IFNs are only induced aftervirus infection of a cell or stimulation ofcertain cell types with type I IFNs andspecific Toll-like receptor (TLR) agonists.The type I IFNs signal through the IFN-areceptor complex (IFNAR), composed ofthe IFNAR1 and IFNAR2 chains. Type IIFN signalling results in the transcriptionof a broad range of anti-viral genes (ISGs)aiming to eliminate or prevent virusreplication. IFN-as are produced morereadily by leukocytes, with dendritic cells(DCs) being powerful inducers of IFN-asupon viral provocation. IFN-b can beproduced by both structural cells andleukocytes and is often first produced atthe site of infection by cells directlyinfected by viruses, where it then signalsthrough IFNAR to induce more of itselfCloseupInterferon-lambda in allergic asthmaDepartment of Respiratory Medicine, UK NationalHeart and Lung Institute, Wright Fleming Insti-tute of Infection and Immunity, and MedicalResearch Council & Asthma UK Centre in AllergicMechanisms of Asthma, Imperial College London,Norfolk Place, London, UK*Corresponding author: Tel: þ44 20 7594 3764,Fax: þ44 207262 8913;E-mail: s.johnston@imperial.ac.ukDOI 10.1002/emmm.201100143306  2011 EMBO Molecular Medicine EMBO Mol Med 3, 306–308 www.embomolmed.organd the IFN-as. The IFN-ls, including IL-29 (IFN-l1), IL-28A (IFN-l2) and IL-28B(IFN-l3) in humans (IL-28A and IL-28Binmice) have similar anti-viral propertiesto the type I IFNs (Meager et al, 2005) asthey induce a similar set of ISGs, but arethought to be expressed preferentially atmucosal surfaces and act on epithelialcells. They use a unique receptor com-plex composed of IFN-lR1a chain (CRF2-12 or IL-28Ra in mice) and IL-10Rb chain(CRF2-4). Previously, the IFN-ls werethought to be strictly regulated by infec-tion, although some data support a role inanti-cancer defense through their anti-proliferative effects. However, whetherIFN-l are induced directly in cancer inthe absence of infection, or by infectionand cancer together, such as in HepatitisB infection and heptocellular carcinoma,is unclear.Koltsida and colleagues utilized micedeficient in the IL-28Ra chain, adminis-tration of exogenous IL-28A and infec-tion with adenovirus encoding IL-28A ina mouse model of sensitization andchallenge to the egg allergen ovalbumin(OVA) to investigate the role of IFN-ls inallergic airway inflammation. Over-expression of IL-28A by adenovirus oradministration of recombinant IL-28A tothe airways resulted in reduced Th2signature cytokines (IL-5 and IL-13),reduced IL-17, but increased IFN-gproduction from mesenteric lymphnode-derived T cell cultures and reducedeosinophil and neutrophil recruitment tothe airways. Mucous staining was alsoreduced and lung function was signifi-cantly improved compared to OVAsensitized and challenged control mice.Interestingly, OVA challenged and sen-sitized mice also revealed low levels ofIL-28A protein in concentrated BAL fluid,suggesting IL-28A may be induced aspart of the allergic cascade. The IL-28Ra/ mice developed strong med-iastinal lymph node-derived Th2 cyto-kine and IL-17 responses after OVAchallenge, increased BAL eosinophilsand neutrophils and decreased lungfunction. Furthermore, experiments withDCs showed that the effect of IL-28 isexerted on CD11cþ DC effector function,and DCs cultured with IL-28A in vitroexpressed high levels of the pro-Th1transcription factor T-bet, whereas, DCsfrom IL-28A adenovirus-treated micepolarized T cells to the Th1 rather thanTh2 phenotype. CD11cþ DCs expressedhigh levels of IL-28Ra mRNA, while RT-PCR analysis and immunohistochemis-try showed that T cells and otherinfiltrating leukocytes within the airwaysdid not express IL-28Ra, clearly suggest-ing that DCs rather than T cells respondto IL-28 in vivo. Finally, the novel effectsof IL-28A on T cell differentiation werenot observed in IFN-gdeficient or micedepleted of IL-12 p40, showing that IL-28A induces Th1 effector function via IL-12 and IFN-g. These findings are ofparticular importance as IL-28 was pre-viously believed to be an anti-viral oranti-cancer cytokine and its powerfulimmunomodulatory effects on DCs indi-cate a wider role for IL-28 in T cellimmunoregulation.The proto-typical Th1 cytokine isIFN-g, produced by and responsible forpolarizing Th1 cells and working in anantagonistic manner to IL-4 and IL-13,the signature cytokines and inducers ofTh2 cells and their responses. The factthat IL-28 induces IFN-g and IL-12 and,therefore, functions in a Th1 polarizingmanner may cause a re-think in thehierarchal order of T cell polarizingcytokines. While how IL-28 fits into thenatural order of Th1, Th2 and Th17 celldevelopment is yet to be thought out indetail; its role in T cell development inallergic asthma (in the absence of infec-tion) is a novel finding. Of particularinterest is how is IL-28 induced in thismodel, by what cell type and in whichanatomical location is the DC receivingIL-28?While the present study shows thatIL-28 is induced by OVA challenge, andclearly shows the effects of IL-28 admin-istration on DC function, the exactmechanism responsible for IL-28 induc-tion in this context remains to beinvestigated. Further, these studies raisethe question whether this ability of IL-28is shared by the type I IFN-b or IFN-a.Early work by Romagnani and colleaguessuggests a similar Th1 skewing potentialof IFN-g and IFN-a (Parronchi et al,1992), but these studies have not beenfollowed through to impact on therapy.While these issues were beyond thescope of the article by Koltsida et al,the discovery of IL-28 as an immunor-egulatory cytokine affecting T cell differ-entiation is important and could poten-tially impact on asthma and allergytreatment.The finding that asthmatics are defi-cient in type I and type III IFNs, with IFN-ls being important in the pathogenesis ofasthma exacerbations has led to theproposal that anti-viral IFNs may beattractive therapies for virus-inducedasthma exacerbations. Indeed, inhaledtype I IFN-b is currently being developedas a novel therapy for asthma exacerba-tions, and has recently entered a phase IIclinical trial. The work of Koltsida et alextends this knowledge and suggests thatsuch therapeutic approaches may not belimited to asthma exacerbations, butcould also be efficacious in non-exacer-bating, stable allergic asthma. The Th2suppressing and Th1 augmenting abilityof IL-28 in mice has implications forhuman asthma and other allergic diseasessuch as rhinitis, as it could be used todampen down or ameliorate Th2 res-ponses to specific allergens. As previouslynoted, anti-Th2 cytokine therapy is not anew approach to allergic asthma; how-ever, in the past only individual cytokineshave been targeted through, for example,anti-IL-5 antibodies or IL-4R antagonismthat targets two cytokines IL-4 and IL-13,which both signal through the IL-4Rachain (O’Byrne et al, 2004). While thesetherapies yielded mixed results in clinicaltrials, IL-28 may offer a subtlety differentapproach in that a Th1 inducing cytokinemay effectively combat the effects of allTh2 cytokines and, thereby, be sufficientto tip the balance of Th1 over Th2 bydirectly modulating DCs that polarizeT cells in the presence of antigen.In summary, Koltsida et al haveidentified IL-28 as a T cell polarizingcytokine in models of allergic asthma.IL-28 acts via CD11cþ DCs, effectivelypromoting Th1 and suppressing Th2CloseupMichael R. Edwards and Sebastian L. Johnston» The work supports theidea that IL-28 may be afuture therapy for both stableallergic asthma and forasthma exacerbations, by itsdual function. . . «www.embomolmed.org EMBO Mol Med 3, 306–308  2011 EMBO Molecular Medicine 307responses. The work is novel and impor-tant, and highlights a previously unknownrole for IL-28, a cytokine normally asso-ciated with the anti-viral response. Thework supports the idea that IL-28 may be afuture therapy for both stable allergicasthma and for asthma exacerbations, byits dual function: controlling allergicasthma through its Th1 modulating abilityand virus-induced asthma exacerbationsthrough its anti-viral activity.The authors declare that they have noconflict of interest.ReferencesContoli M, Message SD, Laza-Stanca V, EdwardsMR, Wark PA, Bartlett NW, Kebadze T, Mallia P,Stanciu LA, Parker HL, et al (2006) Role ofdeficient type III interferon-l production inasthma exacerbations. Nat Med. 12: 1023-1026Koltsida O, Hausding M, Stavropoulos A, Koch S,Tzelepis G, Übel C, Kotenko SV, Sideras P, LehrHA, Tepe M, et al (2011) EMBO Mol Med10.1002/emmm.201100142Meager A, Visvalingam K, Dilger P, Bryan D,Wadhwa M (2005) Biological activity ofinterleukins-28 and -29: comparison with type Iinterferons. Cytokine 31: 109-118O’Byrne PM, Inman MD, Adelroth E (2004)Reassessing the Th2 cytokine basis of asthma.Trends Pharmacol Sci 25: 244-248Parronchi P, De Carli M, Manetti R, Simonelli C,Sampognaro S, Piccinni MP, Macchia D, Maggi E,Del Prete G, Romagnani S (1992) IL-4 and IFN(alpha and gamma) exert opposite regulatoryeffects on the development of cytolyticpotential by Th1 or Th2 human T cell clones. JImmunol 149: 2977-2983Wark PA, Johnston SL, Bucchieri F, Powell R,Puddicombe S, Laza-Stanca V, Holgate ST,Davies DE (2005) Asthmatic bronchial epithelialcells have a deficient innate immune responseto infection with rhinovirus. J Exp Med 201:937-947CloseupInterferon-lambda in allergic asthma308  2011 EMBO Molecular Medicine EMBO Mol Med 3, 306–308 www.embomolmed.org

IL-4 and IFN (alpha and gamma) exert opposite regulatory effects on the development of cytolytic potential by Th1 or Th2 human T cell clones.

Role of deﬁcient type III interferon-l production in asthma exacerbations.

Interferon‐lambda as a new approach for treatment of allergic asthma?

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