title: Exaggerated IL-17 response to epicutaneous sensitization mediates airway inflammation in the absence of IL-4 and IL-13.
abstract: BACKGROUND
  Atopic dermatitis (AD) is characterized by local and systemic T(H)2 responses to cutaneously introduced allergens and is a risk factor for asthma. Blockade of T(H)2 cytokines has been suggested as therapy for AD.
  
  
  OBJECTIVE
  We sought to examine the effect of the absence of IL-4 and IL-13 on the T(H)17 response to epicutaneous sensitization in a murine model of allergic skin inflammation with features of AD.
  
  
  METHODS
  Wild-type, IL4 knockout (KO), IL13 KO and IL4/13 double KO (DKO) mice were subjected to epicutaneous sensitization with ovalbumin (OVA) or saline and airway challenged with OVA. Systemic immune responses to OVA, skin and airway inflammation, and airway hyperresponsiveness were examined.
  
  
  RESULTS
  OVA-sensitized DKO mice exhibited impaired T(H)2-driven responses with undetectable OVA-specific IgE levels and severely diminished eosinophil infiltration at sensitized skin sites but intact dermal infiltration with CD4(+) cells. DKO mice mounted exaggerated IL-17A but normal IFN-gamma and IL-5 systemic responses. Airway challenge of these mice with OVA caused marked upregulation of IL-17 mRNA expression in the lungs, increased neutrophilia in bronchoalveolar lavage fluid, airway inflammation characterized by mononuclear cell infiltration with no detectable eosinophils, and bronchial hyperresponsiveness to methacholine that were reversed by IL-17 blockade. IL-4, but not IL-13, was identified as the major T(H)2 cytokine that downregulates the IL-17 response in epicutaneously sensitized mice.
  
  
  CONCLUSIONS
  Epicutaneous sensitization in the absence of IL-4/IL-13 induces an exaggerated T(H)17 response systemically and in lungs after antigen challenge that results in airway inflammation and airway hyperresponsiveness.
authors.affiliation: Division of Immunology, Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass., USA.
authors.forename: Rui
authors.initials: R
authors.lastname: He
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Juhan
authors.initials: J
authors.lastname: Yoon
authors.forename: Michiko K
authors.initials: MK
authors.lastname: Oyoshi
authors.forename: Andrew
authors.initials: A
authors.lastname: MacGinnitie
authors.forename: Sho
authors.initials: S
authors.lastname: Goya
authors.forename: Eva-Jasmin
authors.initials: EJ
authors.lastname: Freyschmidt
authors.forename: Paul
authors.initials: P
authors.lastname: Bryce
authors.forename: Andrew N J
authors.initials: AN
authors.lastname: McKenzie
authors.forename: Dale T
authors.initials: DT
authors.lastname: Umetsu
authors.forename: Hans C
authors.initials: HC
authors.lastname: Oettgen
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology*; D003876:Dermatitis, Atopic / Q000150:complications* / Q000276:immunology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics*; D020381:Interleukin-17 / Q000276:immunology*; D015847:Interleukin-4 / Q000235:genetics*; D015848:Interleukin-5 / Q000096:biosynthesis / Q000276:immunology; D008168:Lung / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000235:genetics / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D018793:Interleukin-13; D020381:Interleukin-17; D015848:Interleukin-5; D015847:Interleukin-4; D007371:Interferon-gamma; D010047:Ovalbumin