Document Detail

IL-18 induces emphysema and airway and vascular remodeling via IFN-γ, IL-17A, and IL-13.
MedLine Citation:
PMID:  22383501     Owner:  NLM     Status:  MEDLINE    
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.
Min-Jong Kang; Je-Min Choi; Bo Hye Kim; Chang-Min Lee; Won-Kyung Cho; Gina Choe; Do-Hyun Kim; Chun Geun Lee; Jack A Elias
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-03-01
Journal Detail:
Title:  American journal of respiratory and critical care medicine     Volume:  185     ISSN:  1535-4970     ISO Abbreviation:  Am. J. Respir. Crit. Care Med.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-06-04     Completed Date:  2012-08-17     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  9421642     Medline TA:  Am J Respir Crit Care Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1205-17     Citation Subset:  AIM; IM    
Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8056, USA.
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MeSH Terms
Airway Resistance / drug effects
Cytokines / metabolism*
Disease Models, Animal
Flow Cytometry
In Situ Nick-End Labeling
Interleukin-13 / metabolism
Interleukin-17 / metabolism
Interleukin-18 / metabolism*,  pharmacology
Mice, Inbred C57BL
Mice, Transgenic
Pulmonary Disease, Chronic Obstructive / immunology,  metabolism*,  pathology*
Pulmonary Emphysema / immunology,  metabolism*,  pathology*
RNA, Messenger / analysis
Random Allocation
Statistics, Nonparametric
Grant Support
Reg. No./Substance:
0/Cytokines; 0/Interleukin-13; 0/Interleukin-17; 0/Interleukin-18; 0/RNA, Messenger
Comment In:
Am J Respir Crit Care Med. 2012 Jun 1;185(11):1137-9   [PMID:  22661518 ]

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