title: IL-18 induces emphysema and airway and vascular remodeling via IFN-γ, IL-17A, and IL-13.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation, alveolar destruction, and airway and vascular remodeling. However, the mechanisms that lead to these diverse alterations have not been defined.
  
  
  OBJECTIVE
  We hypothesized that IL-18 plays a central role in the pathogenesis of these lesions.
  
  
  METHODS
  We generated and characterized lung-specific, inducible IL-18 transgenic mice.
  
  
  RESULTS
  Here we demonstrate that the expression of IL-18 in the mature murine lung induces inflammation that is associated with the accumulation of CD4(+), CD8(+), CD19(+), and NK1.1(+) cells; emphysema; mucus metaplasia; airway fibrosis; vascular remodeling; and right ventricle cardiac hypertrophy. We also demonstrate that IL-18 induces type 1, type 2, and type 17 cytokines with IFN-γ-inhibiting macrophage, lymphocyte, and eosinophil accumulation while stimulating alveolar destruction and genes associated with cell cytotoxicity and IL-13 and IL-17A inducing mucus metaplasia, airway fibrosis, and vascular remodeling. We also highlight interactions between these responses with IL-18 inducing IL-13 via an IL-17A-dependent mechanism and the type 1 and type17/type 2 responses counterregulating each another.
  
  
  CONCLUSIONS
  These studies define the spectrum of inflammatory, parenchymal, airway, and vascular alterations that are induced by pulmonary IL-18; highlight the similarities between these responses and the lesions in COPD; and define the selective roles that type 1, type 2, and type 17 responses play in the generation of IL-18-induced pathologies.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8056, USA.
authors.forename: Min-Jong
authors.initials: MJ
authors.lastname: Kang
authors.forename: Je-Min
authors.initials: JM
authors.lastname: Choi
authors.forename: Bo Hye
authors.initials: BH
authors.lastname: Kim
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Lee
authors.forename: Won-Kyung
authors.initials: WK
authors.lastname: Cho
authors.forename: Gina
authors.initials: G
authors.lastname: Choe
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Chun Geun
authors.initials: CG
authors.lastname: Lee
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
mesh_terms: D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D018793:Interleukin-13 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D011656:Pulmonary Emphysema / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D018709:Statistics, Nonparametric
chemical_list: D016207:Cytokines; D018793:Interleukin-13; D020381:Interleukin-17; D020382:Interleukin-18; D012333:RNA, Messenger