IL-18 induces emphysema and airway and vascular remodeling via IFN-γ, IL-17A, and IL-13

Am J Respir Crit Care Med. 2012 Jun 1;185(11):1205-17. doi: 10.1164/rccm.201108-1545OC. Epub 2012 Mar 1.

Abstract

Rationale: 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.

Objectives: 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.

Measurements and main 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Airway Resistance / drug effects
  • Animals
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Flow Cytometry
  • Immunoblotting
  • In Situ Nick-End Labeling
  • Interleukin-13 / metabolism
  • Interleukin-17 / metabolism
  • Interleukin-18 / metabolism*
  • Interleukin-18 / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pulmonary Disease, Chronic Obstructive / immunology
  • Pulmonary Disease, Chronic Obstructive / metabolism*
  • Pulmonary Disease, Chronic Obstructive / pathology*
  • Pulmonary Emphysema / immunology
  • Pulmonary Emphysema / metabolism*
  • Pulmonary Emphysema / pathology*
  • RNA, Messenger / analysis
  • Random Allocation
  • Statistics, Nonparametric

Substances

  • Cytokines
  • Interleukin-13
  • Interleukin-17
  • Interleukin-18
  • RNA, Messenger