Nicotine and oxidative cigarette smoke constituents induce immune-modulatory and pro-inflammatory dendritic cell responses☆
Introduction
Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and is the fifth leading cause of death worldwide (Rabe et al., 2007). In the West, the disease is almost always caused by cigarette smoking, which induces chronic airway inflammation associated with irreversible airflow limitation and progressive decline in lung function (Barnes, 2003). The chronically inflamed airways of COPD patients contain several inflammatory cells that persist even in the absence of overt infection (Barnes, 2003). Among the cells know to infiltrate and persist in the lungs of COPD patients are neutrophils, macrophages, B and T lymphocytes, and dendritic cells (DCs) (Barnes, 2003, Demedts et al., 2007). The specific triggers that lead to recruitment and retention of these inflammatory cells are not entirely clear. In addition, the potential roles of inflammatory cells in the lungs of smokers in the development of COPD are not very well defined. Cigarette smokers are also predisposed to develop lung cancer, and COPD itself is an independent risk factor for lung cancer development (Turner et al., 2007), suggesting that smoking-induced chronic lung inflammation may promote tumor growth as well as COPD.
Lung DCs are potent antigen presenting cells distributed in an intra and sub-epithelial location in small airways and have the capacity to profoundly influence both innate and acquired immunity in the lung (Lambrecht et al., 2001). A recent study described significant increase in DC numbers in the small airways of patients with COPD, and found a positive correlation between DC infiltration and disease severity, suggesting a direct pathogenic role for these cells in the COPD lung (Demedts et al., 2007). Potential mechanisms by which DCs may participate in the chronic airway inflammation in COPD are not well understood. In prior studies, we demonstrated that cigarette smoke constituents suppress Th-1 stimulatory functions of DCs while preserving the capacity of DCs to generate interleukin-6 and interleukin-10 upon maturation with lipopolysaccharide (LPS) (Vassallo et al., 2005). The current study was designed to determine mechanisms by which cigarette smoke constituents activate DCs to produce soluble factors that promote local inflammation and immune-suppression in the airways. We sought to identify molecular mechanisms by which DC-mediated chronic inflammation induced by cigarette smoke constituents not only predisposes to chronic airway inflammation, but may additionally promote lung cancer development though epithelial cell transformation. We postulated that cigarette smoke induces the generation of the neutrophilic chemokine CXCL8/IL-8, a central mediator of neutrophil recruitment in human airways (Baggiolini et al., 1989). We also postulated that cigarette smoke constituents induce the production of prostaglandin-E2 (PgE2), an arachidonic acid metabolite that profoundly influences DC function, and has been associated with epithelial cell transformation, an important step in new cancer formation (Yoshimatsu et al., 2001). Furthermore, we postulated that nicotinic stimulation and oxidative stress induced by cigarette smoke to be central mechanisms by which these pro-inflammatory mediators are generated in the airways of smokers, and utilized relevant models and inhibitors to define the relative contribution of oxidative stress and nicotinic stimulation on DCs in inflammatory cell recruitment and prostaglandin generation.
Section snippets
General reagents
Mecamylamine hydrochloride, N-acetyl cysteine (NAC), and bovine catalase were purchased from Sigma biochemicals. CD11c+ magnetic beads were purchased from Miltenyi Biotech. Human recombinant CD40L was purchased from Axxora Platform Biochemicals. Purified hamster anti-mouse CD40 ligating antibody (clone HM40) was purchased from BD Biosciences. Recombinant human and murine IFN-γ and IL-4 were obtained from R&D Systems, while recombinant human GM-CSF was obtained from Immunex. Nicotine was
Cigarette smoke extract stimulates CXCL8 release from immature and maturing DCs
Lung DCs are distributed in sub and intra-epithelial regions of the airways, where neutrophilic influx occurs in COPD (Demedts et al., 2007). To determine whether cigarette smoke induces neutrophilic chemokine production from DCs, human monocyte-derived DCs were incubated with CSE, in the presence or absence of either 100 ng/ml LPS, or 1 μg/ml recombinant human CD40L as maturational agents. In these experiments, a CSE concentration of 1–2% was selected because prior studies demonstrated
Discussion
Although appropriate mucosal inflammation is essential in the protection against pathogens, protracted recruitment of inflammatory cells leads to chronic inflammation, tissue damage and remodeling. COPD is a lung disease characterized by persistent airway inflammation associated with irreversible airflow limitation, excessive mucus production, and progressive decline in lung function (Barnes, 2003). The chronically inflamed airways of COPD patients contain several inflammatory cells including
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Supported by funding from the Parker B Francis Fellowship Foundation, American Lung Association, American Histiocytosis Association, Flight Attendant Medical Research Institute, and Mayo Clinic institutional funds to RV.