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Cytokines in Pulmonary Emphysema: Can Results in Mice Be Translated to Humans?

We appreciate the thoughtful comments of Drs. Bonary, Boutten, and Crestani regarding our article (1), and we welcome the information highlighting their findings in patients with chronic obstructive pulmonary disease (COPD). We agree that mouse models may not always translate to human disease. However, increased numbers of CD8⁺ T cells, alveolar macrophages, and neutrophils are characteristic pathological features of the lungs in COPD, and these cells produce a large amount of inflammatory cytokines, such as IL-8, IFN-, and tumor necrosis factor (TNF)-. In transgenic (Tg) mice, previous studies have reported that overproduction of cytokines in the lungs, including IFN-, TNF-, and IL-13, induced emphysema (2). Based on such observations, we speculated that these cytokines are involved in the pathogenesis of COPD.

We also reported that constitutive overproduction of IL-18 in the lungs of Tg mice resulted in severe emphysema lesions accompanied by increased lung expression of IFN- and IL-13. Disruption of the IL-13 gene, but not the IFN- gene, prevented emphysema and pulmonary inflammation in the Tg mice. Moreover, we reported that a significant correlation existed between serum levels of IL-18 and pulmonary function (%FEV₁) in COPD (3). One very recent paper also reported cigarette smoke–induced IL-18 production in the lungs of mice and that serum levels of IL-18 were increased in COPD (4).

These results suggest that our lung-specific IL-18 Tg mouse is a new model of COPD, as it offers the possibility that IL-13 and IL-18 may play a role in some cases of human COPD. Elias and his colleagues reported that constitutive IL-13 overproduction in the lungs induced pulmonary inflammation, mucus hypersecretion, and lung fibrosis (2). Additionally, conditional lung-specific IL-13 expression with IFN- overproduction in the lungs induces emphysema in adult mice (2). In contrast, we would like to point out that mere in vivo overexpression of IL-18 or IFN- alone is not sufficient to elicit lung disease, since lymphocyte-specific IL-18 Tg mice, skin-specific IL-18 Tg mice, and Tg mice expressing IFN- in bone marrow and thymus (5, 6) did not exhibit pulmonary inflammation or emphysema. Thus, we believe that both the timing and localized production of IFN- and/or IL-13 production may play a role in the initial development and subsequent progression of COPD. Nevertheless, we agree that mouse models of human disease must be evaluated carefully, and certainly further analysis is needed with respect to the role of IL-18, IL-13, and IFN- and/or the MHC phenotype of individuals in the development and progression of pulmonary inflammation and emphysema in COPD.

Tomoaki Hoshino

Kurume University
Kurume, Japan

Howard A. Young

National Cancer Institute–Frederick
Frederick, Maryland

Hisamichi Aizawa

Kurume University
Kurume, Japan

FOOTNOTES

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

REFERENCES

1. Hoshino T, Kato S, Oka N, Imaoka H, Kinoshita T, Takei S, Kitasato Y, Kawayama T, Imaizumi T, Yamada K, et al. Pulmonary inflammation and emphysema: role of the cytokines IL-18 and IL-13. Am J Respir Crit Care Med 2007;176:49–62.[Abstract/Free Full Text]
2. Elias J. The relationship between asthma and COPD: lessons from transgenic mice. Chest 2004;126:111S–116S. [Discussion, 159S–161S.][CrossRef]
3. Kitasato Y, Hoshino T, Kato S, Imaoka H, Young HA, Watanabe K, Shirakusa T, Aizawa H. Enhanced expresssion of IL-18 and its receptor in patients with chronic obstructive pulmonary disease [abstract]. Proc Am Thorac Soc 2006;3:A629.
4. Kang MJ, Homer RJ, Gallo A, Lee CG, Crothers KA, Cho SJ, Rochester C, Cain H, Chupp G, Yoon HJ, et al. IL-18 is induced and IL-18 receptor plays a critical role in the pathogenesis of cigarette smoke-induced pulmonary emphysema and inflammation. J Immunol 2007;178:1948–1959.[Abstract/Free Full Text]
5. Hoshino T, Kawase Y, Okamoto M, Yokota K, Yoshino K, Yamamura K, Miyazaki J, Young HA, Oizumi K. Cutting edge: IL-18-transgenic mice: in vivo evidence of a broad role for IL-18 in modulating immune function. J Immunol 2001;166:7014–7018.[Abstract/Free Full Text]
6. Young HA, Klinman DM, Reynolds DA, Grzegorzewski KJ, Nii A, Ward JM, Winkler-Pickett RT, Ortaldo JR, Kenny JJ, Komschlies KL. Bone marrow and thymus expression of interferon-gamma results in severe B-cell lineage reduction, T-cell lineage alterations, and hematopoietic progenitor deficiencies. Blood 1997;89:583–595.[Abstract/Free Full Text]

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