Mechanism of interleukin-25 (IL-17E)-induced pulmonary inflammation and airways hyper-reactivity

Clin Exp Allergy. 2006 Dec;36(12):1575-83. doi: 10.1111/j.1365-2222.2006.02595.x.


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginase / analysis
  • Arginase / genetics
  • Asthma / immunology
  • Biomarkers / analysis
  • Bronchial Hyperreactivity / immunology
  • Bronchial Provocation Tests
  • Cells, Cultured
  • Chemokine CCL11
  • Chemokines, CC / analysis
  • Chemokines, CC / genetics
  • Cytokines / genetics
  • Cytokines / immunology*
  • Interleukin-13 / genetics
  • Interleukin-13 / immunology
  • Interleukin-17 / immunology
  • Interleukin-17 / pharmacology*
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology
  • Lung / immunology*
  • Lung / pathology
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mucus / metabolism
  • Pneumonia / immunology*
  • Pneumonia / pathology
  • RNA, Messenger / analysis
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT6 Transcription Factor / genetics
  • STAT6 Transcription Factor / immunology
  • Signal Transduction / physiology
  • Th2 Cells / immunology*


  • Biomarkers
  • Ccl11 protein, mouse
  • Chemokine CCL11
  • Chemokines, CC
  • Cytokines
  • Il4ra protein, mouse
  • Interleukin-13
  • Interleukin-17
  • RNA, Messenger
  • Receptors, Cell Surface
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Interleukin-4
  • Arginase