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Abstract
Nuclear Factor (NF)-κB is positioned to provide the interface between COPD and carcinogenesis through regulation of chronic inflammation in the lungs. Using a tetracycline-inducible transgenic mouse model that conditionally expresses activated IκB kinase β (IKKβ) in airway epithelium (IKTA), we found that sustained NF-κB signaling results in chronic inflammation and emphysema by 4 months. By 11 months of transgene activation, IKTA mice develop lung adenomas. Investigation of lung inflammation in IKTA mice revealed a substantial increase in M2-polarized macrophages and CD4+/CD25+/FoxP3+ regulatory T lymphocytes (Tregs). Depletion of alveolar macrophages in IKTA mice reduced Tregs, increased lung CD8+ lymphocytes, and reduced tumor numbers following treatment with the carcinogen urethane. Alveolar macrophages from IKTA mice supported increased generation of inducible Foxp3+ Tregs ex vivo through expression of TGFβ and IL-10. Targeting of TGFβ and IL-10 reduced the ability of alveolar macrophages from IKTA mice to induce Foxp3 expression on T cells. These studies indicate that sustained activation of NF-κB pathway links COPD and lung cancer through generation and maintenance of a pro-tumorigenic inflammatory environment consisting of alternatively activated macrophages and regulatory T cells.
Highlights
Chronic obstructive pulmonary disease (COPD) is the 3rd most common cause of death in the US [1] and is highly associated with an increased risk of lung cancer [2, 3]
We demonstrate that sustained activation of Nuclear Factor (NF)-κB signaling links COPD-like pathology and lung www.impactjournals.com/oncotarget cancer
We found that persistent activation of NF-κB signaling in airway epithelium results in chronic airway inflammation, small airway remodeling, and diffuse lung emphysema, similar to patients with COPD
Summary
Chronic obstructive pulmonary disease (COPD) is the 3rd most common cause of death in the US [1] and is highly associated with an increased risk of lung cancer [2, 3]. Enhanced activation of canonical NF-ĸB signaling has been detected in airway epithelium of COPD patients [5] and in areas of dysplasia and premalignant lesions in biopsies from patients at risk for cancer [6]. We have previously demonstrated that inhibition of NF-κB signaling in the airway epithelium significantly reduces formation of lung tumors [9]. Activation of NF-κB in the lungs markedly increases tumor formation [10], supporting the concept that activation of canonical NF-κB pathway plays an important role in lung carcinogenesis
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