title: T helper-2 immunity regulates bronchial hyperresponsiveness in eosinophil-associated gastrointestinal disease in mice.
abstract: OBJECTIVE
  Eosinophil-associated gastrointestinal diseases are frequently associated with extraintestinal features, including bronchopulmonary manifestations. The factors predisposing to bronchial hyperresponsiveness in eosinophil-associated gastrointestinal diseases are unknown. To elucidate the mechanistic link between eosinophil-associated gastrointestinal diseases and bronchial hyperresponsiveness, we used murine models of eosinophil-associated gastrointestinal diseases and eotaxin-1/transgene-induced eosinophil-associated gastrointestinal diseases.
  
  
  METHODS
  Mice were sensitized and orally challenged with ovalbumin-coated encapsulated particles to induce eosinophil-associated gastrointestinal disease, and bronchial responsiveness was examined. Furthermore, transgenic mice expressing eotaxin in the intestine (with the rat fatty acid-binding promoter) were used to specifically elucidate the contribution of this chemokine in eosinophil-associated gastrointestinal disease-associated bronchial hyperresponsiveness.
  
  
  RESULTS
  The induction of allergen-induced eosinophil-associated gastrointestinal disease was directly correlated with the development of bronchial hyperresponsiveness. The development of bronchial hyperresponsiveness in mice with allergen-induced eosinophil-associated gastrointestinal disease was dependent on eotaxin expression in the gastrointestinal tract. Expression of eotaxin in the gastrointestinal tract of transgenic mice was sufficient to promote bronchial hyperresponsiveness. Bronchial hyperresponsiveness was shown to be directly linked to the aberrant CD4(+) T helper 2 lymphocyte production of interleukin-13. It is interesting to note that transgenic expression of eotaxin was linked with enhanced T helper 2 lymphocyte/cytokine synthesis (interleukin-4, -5, and -13) and the production of mucosal immunoglobulin G1 in the gastrointestinal lumen. We also showed that eotaxin treatment of CD4(+) T cells enhanced interleukin-13 production in vitro.
  
  
  CONCLUSIONS
  These studies suggest that increased expression of eotaxin in the gastrointestinal compartment can lead to increased CD4(+) T cell-derived T helper 2 lymphocyte-cytokine production that drives aberrant immunophysiological responses in distant noninflamed mucosal tissue (the lung). These results provide a possible explanation for the altered lung function seen in some patients with inflammatory gastrointestinal disorders.
authors.affiliation: Allergy and Inflammation Research Group, Division of Molecular Bioscience, The John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Forbes
authors.forename: Vanessa E
authors.initials: VE
authors.lastname: Smart
authors.forename: Angela
authors.initials: A
authors.lastname: D'Aprile
authors.forename: Peter
authors.initials: P
authors.lastname: Henry
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Klaus I
authors.initials: KI
authors.lastname: Matthaei
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hogan
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000150:complications / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000276:immunology; D004804:Eosinophils / Q000276:immunology; D050556:Fatty Acid-Binding Proteins; D005767:Gastrointestinal Diseases / Q000150:complications / Q000276:immunology*; D007136:Immunoglobulins / Q000276:immunology; D018793:Interleukin-13 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D051381:Rats; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; C515457:Ccl11 protein, mouse; C515458:Ccl11 protein, rat; D054413:Chemokine CCL11; D019742:Chemokines, CC; D050556:Fatty Acid-Binding Proteins; D007136:Immunoglobulins; D018793:Interleukin-13