Work

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

Year: 2015

Type: article

Abstract: // Rinat Zaynagetdinov 1 , Taylor P. Sherrill 1 , Linda A. Gleaves 1 , Pierre Hunt 1 , Wei Han 1 , Allyson G. McLoed 2 , Jamie A. Saxon 2 , Harikrishna Tanjore 1 , Peter M. Gulleman 4 , Lisa R. Young 1, 4 , Timothy S. Blackwell 1, 2, 3 1 Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA, 37232 2 Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA, 37232 3 U.S. Department of Veterans Affairs, Nashville, TN, USA, 37232 4 Division of Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA, 37232 Correspondence to: Rinat Zaynagetdinov, e-mail: [email protected] Keywords: NF-κB, COPD, lung cancer, macrophage, tregs Received: September 16, 2015 Accepted: December 02, 2015 Published: December 11, 2015 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.6562