Research Papers:

Chronic NF-κB activation links COPD and lung cancer through generation of an immunosuppressive microenvironment in the lungs

Rinat Zaynagetdinov _, Taylor P. Sherrill, Linda A. Gleaves, Pierre Hunt, Wei Han, Allyson G. McLoed, Jamie A. Saxon, Harikrishna Tanjore, Peter M. Gulleman, Lisa R. Young and Timothy S. Blackwell

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Oncotarget. 2016; 7:5470-5482. https://doi.org/10.18632/oncotarget.6562

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Rinat Zaynagetdinov1, Taylor P. Sherrill1, Linda A. Gleaves1, Pierre Hunt1, Wei Han1, Allyson G. McLoed2, Jamie A. Saxon2, Harikrishna Tanjore1, Peter M. Gulleman4, Lisa R. Young1,4, Timothy S. Blackwell1,2,3

1Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA, 37232

2Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA, 37232

3U.S. Department of Veterans Affairs, Nashville, TN, USA, 37232

4Division of Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA, 37232

Correspondence to:

Rinat Zaynagetdinov, e-mail: rinat.z.zaynagetdinov@vanderbilt.edu

Keywords: NF-κB, COPD, lung cancer, macrophage, tregs

Received: September 16, 2015    Accepted: December 02, 2015    Published: December 11, 2015


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.

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