Epithelial nuclear factor-κB signaling promotes lung carcinogenesis via recruitment of regulatory T lymphocytes.

Abstract

The mechanisms by which chronic inflammatory lung diseases, particularly chronic obstructive pulmonary disease, confer enhanced risk for lung cancer are not well-defined. To investigate whether nuclear factor (NF)-κB, a key mediator of immune and inflammatory responses, provides an interface between persistent lung inflammation and carcinogenesis, we utilized tetracycline-inducible transgenic mice expressing constitutively active IκB kinase β in airway epithelium (IKTA (IKKβ trans-activated) mice). Intraperitoneal injection of ethyl carbamate (urethane), or 3-methylcholanthrene (MCA) and butylated hydroxytoluene (BHT) was used to induce lung tumorigenesis. Doxycycline-treated IKTA mice developed chronic airway inflammation and markedly increased numbers of lung tumors in response to urethane, even when transgene expression (and therefore epithelial NF-κB activation) was begun after exposure to carcinogen. Studies using a separate tumor initiator/promoter model (MCA+BHT) indicated that NF-κB functions as an independent tumor promoter. Enhanced tumor formation in IKTA mice was preceded by increased proliferation and reduced apoptosis of alveolar epithelium, resulting in increased formation of premalignant lesions. Investigation of inflammatory cells in lungs of IKTA mice revealed a substantial increase in macrophages and lymphocytes, including functional CD4+/CD25+/FoxP3+ regulatory T lymphocytes (Tregs). Importantly, Treg depletion using repetitive injections of anti-CD25 antibodies limited excessive tumor formation in IKTA mice. At 6 weeks following urethane injection, antibody-mediated Treg depletion in IKTA mice reduced the number of premalignant lesions in the lungs in association with an increase in CD8 lymphocytes. Thus, persistent NF-κB signaling in airway epithelium facilitates carcinogenesis by sculpting the immune/inflammatory environment in the lungs.

• Authors: R Zaynagetdinov, G T Stathopoulos, T P Sherrill, D-S Cheng, A G McLoed, J A Ausborn, V V Polosukhin, L Connelly, W Zhou, B Fingleton, R S Peebles, L S Prince, F E Yull, T S Blackwell
• Journal: Oncogene (Oncogene) Vol. 31 Issue 26 Pg. 3164-76 (Jun 28 2012) ISSN: 1476-5594 [Electronic] England
• PMID: 22002309 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• NF-kappa B
• Urethane

Topics

• Animals
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chronic Disease
• Epithelium (drug effects, immunology, metabolism, pathology)
• Humans
• Inflammation (immunology, metabolism, pathology)
• Lung (drug effects, immunology, metabolism, pathology)
• Lung Neoplasms (chemically induced, immunology, metabolism, pathology)
• Mice
• NF-kappa B (metabolism)
• Paracrine Communication (drug effects)
• Signal Transduction
• T-Lymphocytes, Regulatory (drug effects, immunology)
• Time Factors
• Urethane (adverse effects)