title: Mechanism of interleukin-25 (IL-17E)-induced pulmonary inflammation and airways hyper-reactivity.
abstract: BACKGROUND
  IL-25, a novel member of the IL-17 cytokine family, promotes CD4+ T-helper 2 lymphocyte-like (Th type-2) inflammatory responses in the lung. Although IL-25 up-regulates IL-13 in the lung, the contribution of this and other type 2 cytokine signalling pathways to the induction and persistence of airways hyper-reactivity (AHR) and allergic inflammation are unclear.
  
  
  OBJECTIVE
  To determine the downstream factors employed by IL-25 to induce Th type-2 pulmonary inflammation and AHR.
  
  
  METHODS
  IL-25 was delivered to the airways of BALB/c mice by intra-tracheal (i.t.) instillation and AHR and Th type-2 inflammatory responses were characterized in wild type (WT) and Th type-2-cytokine and -signalling pathway-deficient (-/-) mice.
  
  
  RESULTS
  IL-25 treatment resulted in AHR, eosinophilic inflammation, mucus hypersecretion and a progressive increase in the production of Th type-2 cytokines in the lungs. Levels of arginase-I (arg-I) and eotaxin were also elevated by IL-25 treatment. A significant reduction in AHR, and attenuation of mucus production was observed in IL-25-treated IL-13-/-, IL-4 receptor alpha (IL-4Ralpha-/-)- and signal-transducer-and-activator-of-transcription-factor-6 (STAT6-/-)-deficient mice. AHR was also inhibited in IL-4(-/-)- and IL-5/eotaxin(1)(-/-)- deficient mice treated with IL-25, however, mucus hypersecretion was not completely ablated. IL-25 promoted Th type-2 responses by directly acting on naïve T cells.
  
  
  CONCLUSIONS
  IL-25 potently (single dose) induces sustained AHR and acute pulmonary inflammation with eosinophilia. IL-25-induced AHR is dependent on the production of Th type-2 cytokines, and removal of IL-13 and its signal transduction pathway prevents IL-25-induced airways inflammation and AHR. IL-25 potently induces inflammatory cascades that may exacerbate allergic airways inflammation by promoting Th type-2 cytokine responses in conjunction with the up-regulation of factors (eotaxin and arg-I) that can amplify inflammation associated with allergic disorders. Dysregulation in IL-25 production may predispose to features of allergic airways disease.
authors.affiliation: Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Sharkhuu
authors.forename: K I
authors.initials: KI
authors.lastname: Matthaei
authors.forename: E
authors.initials: E
authors.lastname: Forbes
authors.forename: S
authors.initials: S
authors.lastname: Mahalingam
authors.forename: S P
authors.initials: SP
authors.lastname: Hogan
authors.forename: P M
authors.initials: PM
authors.lastname: Hansbro
authors.forename: P S
authors.initials: PS
authors.lastname: Foster
mesh_terms: D000818:Animals; D001119:Arginase / Q000032:analysis / Q000235:genetics; D001249:Asthma / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D016535:Bronchial Hyperreactivity / Q000276:immunology; D001985:Bronchial Provocation Tests; D002478:Cells, Cultured; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000032:analysis / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology / Q000494:pharmacology*; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009093:Mucus / Q000378:metabolism; D011014:Pneumonia / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology; D018418:Th2 Cells / Q000276:immunology*; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D001119:Arginase; D015415:Biomarkers; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines; D018793:Interleukin-13; D020381:Interleukin-17; D015847:Interleukin-4; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D050800:STAT6 Transcription Factor; C515457:Ccl11 protein, mouse; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C494100:Stat6 protein, mouse