title: Chronic NF-κB activation links COPD and lung cancer through generation of an immunosuppressive microenvironment in the lungs.
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.
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232 USA.
authors.forename: Rinat
authors.initials: R
authors.lastname: Zaynagetdinov
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232 USA.
authors.forename: Taylor P
authors.initials: TP
authors.lastname: Sherrill
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232 USA.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Gleaves
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232 USA.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hunt
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232 USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, 37232 USA.
authors.forename: Allyson G
authors.initials: AG
authors.lastname: McLoed
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, 37232 USA.
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Saxon
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232 USA.
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Tanjore
authors.affiliation: Division of Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, 37232 USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Gulleman
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232 USA.|Division of Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, 37232 USA.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Young
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232 USA.|Department of Cancer Biology, Vanderbilt University, Nashville, TN, 37232 USA.|U.S. Department of Veterans Affairs, Nashville, TN, 37232 USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D004848:Epithelium / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology; D007166:Immunosuppressive Agents / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D016328:NF-kappa B; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D051550:I-kappa B Kinase
keywords: COPD; NF-κB; lung cancer; macrophage; tregs