Pulmonary inflammation and emphysema: role of the cytokines IL-18 and IL-13.
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is believed to be an inflammatory cytokine-driven disease, but a causal basis that can be associated with a specific cytokine has not been directly demonstrated. We have previously reported that proinflammatory cytokine IL-18 expression is important in the pathogenesis of pulmonary inflammation and lung injury in mice. Our results demonstrate that IL-18 overproduction in the lungs can induce lung diseases, such as pulmonary inflammation, lung fibrosis, and COPD.


OBJECTIVE
We analyzed the role of IL-18 in the pathogenesis of COPD.


METHODS
Using the human surfactant protein C promoter to drive expression of mature mouse IL-18 cDNA, we developed two different lines of transgenic (Tg) mice that overproduced mouse mature IL-18 in the lungs either constitutively or in response to doxycycline.


RESULTS
Constitutive overproduction of IL-18 in the lungs resulted in the increased production of IFN-gamma, IL-5, and IL-13, and chronic pulmonary lung inflammation with the appearance of CD8+ T cells, macrophages, neutrophils, and eosinophils. Increased lung volume, severe emphysematous change, dilatation of the right ventricle, and mild pulmonary hypertension were observed in (more than 15-wk-old) Tg mice. Interestingly, disruption of the IL-13 gene, but not the IFN-gamma gene, prevented emphysema and pulmonary inflammation in Tg mice. Moreover, when IL-18 production was induced in lung tissues for 4 weeks through the use of a doxycycline-dependent surfactant protein C promoter, interstitial inflammation was induced.


CONCLUSIONS
Our results indicate that IL-18 and IL-13 may have an important role in the pathogenesis of COPD.
Hoshino
Tomoaki
T
Department of Internal Medicine 1, Kurume University School of Medicine, Kurume, Japan. hoshino@med.kurume-u.ac.jp
Kato
Seiya
S
Oka
Naoki
N
Imaoka
Haruki
H
Kinoshita
Takashi
T
Takei
Satoko
S
Kitasato
Yasuhiko
Y
Kawayama
Tomotaka
T
Imaizumi
Tsutomu
T
Yamada
Kentaro
K
Young
Howard A
HA
Aizawa
Hisamichi
H
D000818:Animals; D004195:Disease Models, Animal; D004646:Emphysema / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D018793:Interleukin-13 / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011014:Pneumonia / Q000276:immunology / Q000473:pathology; D011650:Pulmonary Alveoli / Q000276:immunology / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000503:physiopathology
D018793:Interleukin-13; D020382:Interleukin-18