Published ahead of print on March 30, 2007, doi:10.1164/rccm.200603-316OC
Am. J. Respir. Crit. Care Med., Volume 176, Number 1, July 2007, 49-62
A more recent version of this article appeared on July 1, 2007
Submitted on March 3, 2006
Accepted on March 29, 2007
Pulmonary Inflammation and Emphysema: Role of the Cytokines IL-18 and IL-13
Tomoaki Hoshino1*, Seiya Kato2, Naoki Oka3, Haruki Imaoka4, Takashi Kinoshita4, Satoko Takei4, Yasuhiko Kitasato4, Tomotaka Kawayama4, Tsutomu Imaizumi5, Kentaro Yamada6, Howard A Young7, and Hisamichi Aizawa4
1 Department of Internal Medicine 1, Kurume University School of Medicine, Kurume, Fukuoka, Japan; Laboratory of Experimental Immunology, National Cancer Institute, Center for Cancer Research, Frederick, MD, USA,
2 Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan; Division of Pathology and Cell Biology, Graduate School and the Faculty of Medicine, University of the Ryukyus, Okinawa, Japan,
3 Department of Internal Medicine 3 and the Cardiovascular Research Institute, Kurume University School of Medicine, Kurume, Fukuoka, Japan,
4 Department of Internal Medicine 1, Kurume University School of Medicine, Kurume, Fukuoka, Japan,
5 Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan,
6 Department of Endocrinology and Metabolism, Kurume University School of Medicine, Kurume, Fukuoka, Japan,
7 Laboratory of Experimental Immunology, National Cancer Institute, Center for Cancer Research, Frederick, MD, USA
* To whom correspondence should be addressed. E-mail: hoshino{at}med.kurume-u.ac.jp.
Rationale: COPD is thought 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 proinflammatory cytokine IL-18 expression is important in the pathogenesis of pulmonary inflammation and lung injury in mice. Our results demonstrate IL-18 overproduction in the lungs can induce lung diseases such as pulmonary inflammation, lung fibrosis, and COPD.
Objectives: We analyzed the role of IL-18 in the pathogenesis of COPD.
Methods: Utilizing the human surfactant protein C promoter SP-C to drive expression of mature mouse IL-18 cDNA, we developed two different lines of transgenic 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- ,IL-5, and IL-13, and chronic pulmonary lung inflammation with the appearance of CD8+ T cells, macrophages, neutrophils, and eosinophils. Enlarged lung volume, severe emphysematous change, dilatation of the right ventricle, and mild pulmonary hypertension were observed in aged Tg mice. Interestingly, disruption of the IL-13 gene but not the IFN- gene prevented emphysema and pulmonary inflammation in aged Tg mice. Moreover, when IL-18 production was induced in lung tissues for 4 weeks through the use of a doxycycline-dependent SP-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.
Key words: emphysema, IL-18, IL-13, IFN-, transgenic mouse
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