It has been reported that Th17 cells are a critical component of the adaptive immune response and IL-17 has been implicated in chronic inflammatory and autoimmune diseases [13, 14]. There has been much interest in the role of the adaptive immune response in COPD since COPD in humans is associated with the development of lymphoid follicles in the lung [3, 4]. Moreover, patients with COPD have evidence of anti-elastin antibodies and Th1 responses, suggesting an autoimmune component [8, 9]. Recently, numbers of IL-17A+ cells in the airways [18–20, 36] and peripheral blood  of COPD patients have been reported to be increased. These studies suggested an association between Th17 and COPD, however, the role for IL-17A in disease development is not defined.
In the present study, to elucidate the role of IL-17A in the development of emphysema, we investigated PPE-induced initial inflammation and subsequent late phase emphysematous change in IL-17A−/− and WT mice. We demonstrated that both the PPE-induced acute phase inflammation and the late phase emphysematous changes seen in WT mice were attenuated in IL-17A−/− mice. Increased levels of neutrophil-related chemokines such as KC, MIP-2 and IL-1β seen in the BAL fluid of WT mice were also significantly reduced in IL-17A−/− mice following PPE administration. These data, for the first time, indicated that IL-17A may play a role in the elastase-induced pulmonary pathology.
We observed that levels of IL-17A in the lungs were increased in the acute phase following PPE treatment. The numbers of IL-17A producing cells in the lung were also increased following PPE treatment. Thus, elastase administration leads to increases in both IL-17-producing cells and levels of IL-17A. These results were consistent with the observations showing that IL-17A expressing cells were increased in the airways of COPD patients. For example, numbers of IL-17A+ cells in the bronchial submucosa were increased in COPD compared to smokers without COPD and nonsmoking control subjects . The sputum concentrations of IL-17A in COPD were increased compared to patients with asthma . It has also been reported that cigarette smoke extract had an adjuvant effect on CD4 T cell activation and differentiation to Th17 cells in vitro . These data suggest that smoking induces both IL-17A secretion in the airways and increases differentiation of Th17 cells.
IL-17A has been shown to accumulate  and activate neutrophils , and enhance epithelial production of IL-8 . It has also been reported that IL-17A acts directly on epithelial cells, airway fibroblasts and smooth muscle cells to induce the secretion of neutrophil-recruiting chemokines . Airway smooth muscle strips from COPD patients expressed IL-17RA and responded to IL-17A by inducing IL-8 production . Rodents lack a direct homologue of IL-8, but the chemokines KC and MIP-2 are regarded as functional homologues and have been found to contribute to the pathology of a number of neutrophil-dependent animal models of disease . In the present study, levels of KC and MIP-2 were increased in WT mice following PPE treatment, and these levels were lower in IL-17A−/− mice. Thus IL-17A may induce neutrophil chemotactic factor production, KC and MIP-2, and contribute to neutrophilic airway inflammation following PPE treatment.
Th17 cells have been shown to produce more inflammatory cytokines, such as IL-1β, compared with regulatory T cells and other T-helper cells . In the present study, the levels of IL-1β in WT mice were increased 4 days after intratracheal PPE instillation and levels were significantly lower in IL-17A−/− mice. Although the link between acute inflammatory changes and the subsequent development of emphysematous changes requires further investigation, it is likely that in addition to KC and MIP-2, increased levels of proinflammatory cytokines such as IL-1β prolong and enhance acute inflammation and contribute to later emphysema. In this way, IL-17A-mediated pathways might play a central role in the pathophysiological events.
Chen et al. recently reported that IL-17RA-deficient mice failed to develop emphysema after 6 months of cigarette smoke exposure in contrast to wild-type mice . In their study, the wild-type mice which received 6 months smoking exposure showed higher levels of IL-17 in BAL fluid compared to sham-exposed mice. IL-17RA−/− mice showed lower levels of monocyte chemotactic protein-1 (MCP-1) in BAL fluid and lower expression of the matrix metalloproteinase (MMP)-9 and MMP-12 in the lung, compared to wild-type mice, suggesting an important role for IL-17RA in macrophage recruitment to the inflamed lung and for development of emphysema. They saw no differences in KC levels in BAL fluid between IL-17RA−/− mice and wild-type mice when emphysema was established, similar to our study. In the present study, however, we have shown that neutrophil-related chemokines such as KC and MIP-2 were increased at a relatively early stage following elastase treatment, which was associated with increased levels of IL-17A, and increased numbers of neutrophils in the airways, suggesting an important role for IL-17A in the recruitment of neutrophils at a relatively early stage. IL-17RA has at least three ligands including IL-17A, IL-17 F, and IL-25. In the present study, we demonstrated the importance of IL-17A for emphysema using IL-17A−/− mice. Shan et al. have also shown that cigarette smoke-induced emphysema is mediated by IL-17A in mice . Regarding other ligands for IL17RA, IL-25 has been reported to be associated with both Th2 and Th17 immune responses , however, little is known about the role of this cytokine in emphysema development. Expression of both IL-17A and IL-17 F were increased in the airways of COPD subjects in both inflammatory cells as well as in the airway epithelium [18, 19]. In contrast, numbers of IL-17 F+ cells were not increased in COPD compared to control subjects .
In the present study, elastase-induced emphysematous changes of the lung in IL-17A−/− mice were reduced, but not completely attenuated compared to WT mice, suggesting that IL-17A may be essential but not sufficient for the full development of elastase-induced emphysema. Previous studies have shown that Th1 cells contribute largely to the inflammatory cascade of events related to the pathogenesis of COPD [34, 35]. It has also been reported that Th2 cells may be important in the inflammatory response of the disease [47–49]. Using IL-18 transgenic mice with disruption of the IL-13 gene, Hoshino et al. have shown that IL-18 and IL-13 might have important roles in the pathogenesis of emphysema . Recently, it has also been reported that overexpression of IL-18 induced emphysema via IFN-γ and IL-17A, and induced mucus metaplasia via IL-13 . Chronic cigarette smoke has been shown to induce both Th1 and Th17 cells in mice . Thus, although Th17 cells may play an important role in the pathogenesis of emphysema, their role is not exclusive and Th1 and Th2 cells may also have contributory roles. Further understanding of how these helper T cell subsets interact and orchestrate a pathological response to smoking will be essential if we are to successfully intervene in the development and progression of COPD and emphysema.