title: Eotaxin-2 and IL-5 cooperate in the lung to regulate IL-13 production and airway eosinophilia and hyperreactivity.
abstract: BACKGROUND
  Eotaxin-2 is a member of the eotaxin subfamily of CC chemokines that display eosinophil-specific, chemotactic properties and has been associated with allergic disorders. However, the contribution of eotaxin-2 to the development of defined pathogenic features of allergic disease remains to be defined.
  
  
  OBJECTIVE
  We sought to determine whether eotaxin-2 was a cofactor with IL-5 for the regulation of pulmonary eosinophilia and to identify the combined role of these molecules in the induction of phenotypic characteristics of allergic lung disease.
  
  
  METHODS
  We instilled recombinant eotaxin-2 into the airways of wild-type mice that had been treated systemically with IL-5 or into IL-5-transgenic mice and characterized pulmonary eosinophil numbers, IL-13 production, and airway hyperreactivity (AHR) to methacholine. Mice deficient in the IL-4 receptor alpha-chain, IL-13, and signal transducers and activators of transcription 6 or mice treated with anti-CCR3 monoclonal antibody were also used.
  
  
  RESULTS
  Eotaxin-2 and IL-5 cooperatively promoted eosinophil accumulation, IL-13 production, and AHR to methacholine. Neither eotaxin-2 nor IL-5 alone induced these features of allergic disease. IL-13 production was critically dependent on eotaxin-2- and IL-5-regulated eosinophilia, which predisposed to the development of AHR. AHR was dependent on IL-13 and signaling through the IL-4R alpha-chain and signal transducers and activators of transcription 6 pathways and the presence of eosinophils in the lung.
  
  
  CONCLUSIONS
  These investigations demonstrate important cooperativity between eotaxin-2, IL-5, and IL-13 signaling systems and eosinophils for the development of hallmark features of allergic disease of the lung.
authors: Division of Molecular Biosciences, The John Curtin School of Medical Research, Australian National University, Canberra, ACT.
authors: Ming
authors: M
authors: Yang
authors: Simon P
authors: SP
authors: Hogan
authors: Surendran
authors: S
authors: Mahalingam
authors: Sam M
authors: SM
authors: Pope
authors: Nives
authors: N
authors: Zimmermann
authors: Patricia
authors: P
authors: Fulkerson
authors: Lindsay A
authors: LA
authors: Dent
authors: Ian G
authors: IG
authors: Young
authors: Klaus I
authors: KI
authors: Matthaei
authors: Marc E
authors: ME
authors: Rothenberg
authors: Paul S
authors: PS
authors: Foster
mesh_terms: D000336:Aerosols; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000503:physiopathology; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage; D054423:Chemokine CCL24; D019742:Chemokines, CC / Q000008:administration & dosage; D004357:Drug Synergism; D004804:Eosinophils / Q000473:pathology; D007322:Instillation, Drug; D018793:Interleukin-13 / Q000096:biosynthesis*; D015848:Interleukin-5; D007958:Leukocyte Count; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D016210:Methacholine Chloride / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout / Q000235:genetics; D008822:Mice, Transgenic / Q000235:genetics; D011657:Pulmonary Eosinophilia / Q000139:chemically induced* / Q000473:pathology; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000172:deficiency / Q000378:metabolism
chemical_list: D000336:Aerosols; D016085:Bronchoconstrictor Agents; C515485:Ccl24 protein, mouse; D054423:Chemokine CCL24; D019742:Chemokines, CC; D018793:Interleukin-13; D015848:Interleukin-5; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D016210:Methacholine Chloride