It has been suggested that IL-18 may play an important role in the pathophysiology of patients with asthma. Higher serum levels of IL-18 have been previously identified in asthmatic subjects in comparison to healthy control subjects 
. In addition, significantly higher serum IL-18 levels have been reported in patients with acute severe asthma 
. An IL-18 gene polymorphism was reported to be associated with asthma severity; the rs5744247 variant reflecting both higher transcriptional activity and higher serum IL-18 levels 
. In addition, the IL-18R gene (on 2q21) has been identified as a candidate gene associated with increased susceptibility to asthma in children 
, and polymorphisms of the gene are related to allergic asthma and airway hyper-responsiveness (AHR) 
. We found that the IL-18 protein was strongly expressed in airway epithelium cells and smooth muscle cells in airway biopsy samples from allergic asthmatic subjects. Moreover, serum levels of IL-18 were significantly higher in the asthmatic subjects than in either the non-asthmatic allergic subjects or the healthy controls 
. In contrast, IL-18Rα was weakly expressed in the airway epithelium, and not on airway smooth muscle cells. In this study, we showed that AHR and airway inflammatory cells accompanied with CD4+
T cells, CD8+
T cells and eosinophils were significantly increased in IL-18 Tg mice sensitized– and challenged– with OVA (OVA/OVA–IL-18 Tg mice), as compared to control WT mice. Treatment with anti-CD4 mAb significantly decreased the number of lymphocytes and AHR in the lungs of OVA/OVA–IL-18 Tg mice, as compared to control Ab treated OVA/OVA–IL-18 Tg mice. The intracellular staining analysis revealed that overproduction of IL-18 protein in the lungs induces IL-13 but not IFN-γ in CD4+
T cells. We utilized anti-CD4 mAb and IL-13 gene deficient (−/−) mice, and shown reduced airway inflammation and AHR following OVA-challenge in the IL-18 Tg mice. Our data shows that overproduction of IL-18 protein in the lungs increases pulmonary inflammation accompanied with IL-13 producing CD4+
T cells, and results in increasing AHR in this mouse asthma model.
Previously, we showed that constitutive overproduction of mature IL-18 protein in the lungs of B6 background transgenic mice resulted in the increased production of IFN-γ IL-5, and IL-13,
and severe emphysema accompanied by pulmonary inflammation, especially by CD8+
T cells. Moreover, disruption of the IL-13 but not IFN-γ gene prevented emphysema and pulmonary inflammation in IL-18 Tg mice 
. A recent study by Kang and colleagues demonstrated that the inducible expression of IL-18 in the mature murine lung induces pulmonary inflammation with the accumulation of CD4+
cells, emphysema, mucus metaplasia, airway fibrosis, vascular remodeling and right ventricle cardiac hypertrophy in B6 mice. Moreover, disruption of the IL-13, IL-17 gene, but not the IFN-γ gene prevented emphysema and pulmonary inflammation in IL-18 Tg mice 
. We previously reported that in vivo
overexpression of IL-18 alone is not sufficient to elicit lung disease, since lymphocyte-specific IL-18 B6 Tg mice 
, and skin-specific IL-18 B6 Tg mice 
did not exhibit pulmonary inflammation or emphysema. Additionally, conditional lung-specific IL-13 expression with IFN-γ overproduction in the lungs induces emphysema in adult mice 
. In this study, we established lung-specific IL-18 Tg mice Balb/c background by backcrossing the B6 lung-specific IL-18 Tg mice with WT Balb/c mice. Expression levels of IL-18 and IFN-γ but not IL-13 were increased in the lungs of Balb/c IL-18 Tg mice. Histological analysis found that the lung tissues of Balb/c IL-18 Tg mice were quite normal. Thus, we believe that localized production of IL-18 in the lungs may play an important role in the development of pulmonary inflammation and emphysema via IL-13 production in mice as well as COPD patients. Further studies will be needed to elucidate the molecular mechanisms involved with the lack of IL-13 gene expression in the lungs of Balb/c IL-18 Tg mice.
IL-18 was reported to take part in the differentiation of Th17 cells by amplifying IL-17 production by polarized Th17 cells in synergy with IL-23 
. As described above, the inducible expression of IL-18 in the lungs induces pulmonary inflammation, emphysema, mucus metaplasia, airway fibrosis, vascular remodeling and right ventricle cardiac hypertrophy in adult B6 mice using the CC10 promoter. In addition, disruption of the IL-17 gene prevented emphysema and pulmonary inflammation in the B6 IL-18 Tg mice 
. In this study, there was no significant difference in the expression levels of IL-5, IL-12p70, and eotaxin between OVA/OVA–IL-18 Tg and OVA/OVA–WT mice. Moreover, IL-17A/F was under detectable level in the BALFs of OVA/OVA–IL-18 Tg and WT mice, suggesting that Th17 cells may not play a role in our mouse asthma model. However, there are several studies that have demonstrated the important effects of IL-17 in the pathogenesis of asthma 
. It has been shown that many of these cytokine responses are very transient, so. it is possible that the response was earlier or later and that the transgenic mouse response kinetics may not be the same as the wild type mouse. Further analysis will be needed to address this issue.
Currently, therapeutic approaches for steroid-resistant uncontrolled asthma are limited 
. Our present results suggest that overexpression of IL-18 in the lungs may induced pulmonary inflammation and AHR, and result in exacerbating the disease activities in patients with asthma. Blocking of IL-18 expression may be feasible in vivo
. IL-18 inhibitors, including caspase-1 inhibitors, anti-human IL-18 monoclonal antibodies, anti-human IL-18R monoclonal antibodies, soluble IL-18 receptor complex 
and/or IL-18 binding protein (BP) 
may be clinically beneficial for the treatment of patients with steroid-resistant asthma, for whom current treatment options are very limited.