Abstract
IFN-γ-producing CD4+ T (Th1) cells and IL-17-producing CD4+ T (Th17) cells play a critical role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the immune regulation between Th1 and Th17 cells remains unclear. Previous studies have demonstrated that interleukin-27 (IL-27)/WSX-1 exerted pro- or anti-inflammatory effects in many acute inflammatory diseases by modulating T cell-mediated immune response, but little was known about its role in chronic inflammatory disease, especially in smoking-related lung diseases. Considering IL-27 is an important regulator in T lymphocytes immune responses and was found markedly increased in patients with COPD, we hypothesized that IL-27/WSX-1 may exert immuno-regulatory effects on the differentiation of Th1 and Th17 cells in smoking-related COPD. In this study, we aimed to evaluate the expression of IL-27 in patients with COPD and explore the role of IL-27/WSX-1 on Th1 and Th17 cells differentiation in a smoking mouse model of emphysema. We found that elevated expression of IL-27 was associated with increased proportion of Th1 cells and Th17 cells in patients with COPD and demonstrated parallel findings in cigarette smoke-exposed mice. In addition, cigarette smoke exposure upregulated the expression of IL-27R (WSX-1) by naive CD4+ T cells in mice. In vitro, IL-27 significantly augmented the secretion of IFN-γ by naive CD4+ T cells via a T-bet, p-STAT1, and p-STAT3-dependent manner, but inhibited the production of IL-17 by a ROR-γt and p-STAT1-dependent way. Furthermore, anti-IL27 treatment dramatically decreased the expression of IFN-γ-producing CD4+ T cells in cigarette smoke-exposed mice. These findings proposed that IL-27 has functions for promoting the expression of Th1 cells but inhibiting the expression of Th17 cells in vitro and IL-27 neutralization-attenuated Th1-mediated inflammation in vivo, suggesting targeting IL-27/WSX-1 may provide a new therapeutic approach for smoking-related COPD.
Highlights
Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation and destruction of lung parenchyma
We found that IL-17+IFN-γ+CD4+ T cells were significantly higher in COPD patients
Chronic inflammation in the airways and the lung parenchyma which mainly triggered by cigarette smoke is the most remarkable characteristic of COPD
Summary
Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation and destruction of lung parenchyma. Tobacco smoking is recognized as the most important risk factor for COPD. Despite increased awareness and concerns of smoking hazards in general population, the global burden of smoking-related lung diseases (e.g., COPD, chronic bronchitis, and lung cancer) continues to increase in worldwide. COPD is expected to become the third leading cause of death worldwide by 2020 and imposes a heavy burden on health-care systems, the precise pathogenesis of smoking-related COPD has not yet been fully elucidated. It has been well established that COPD exhibited a predominant IFN-γ-producing T (Th1/Tc1) cell cytokine pattern [6,7,8]. In our recent studies and with others, data revealed that Th17 cells were exaggerated in COPD [9,10,11]. Relatively little is known about the regulatory mechanism between Th1 and Th17 cells
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