Abstract 529: Impaired NF-κB signaling in myeloid cells enhances urethane-induced lung carcinogenesis

Abstract

Abstract Nuclear Factor κB (NF-κB) regulates airway inflammation and has been implicated in lung tumorigenesis. We and others have previously described a pro-tumorigenic role for NF-κB activity in airway epithelial cells. However, the role of NF-κB signaling in other cell types, including myeloid cells, in modulation of lung tumorigenesis is unknown. The goal of these studies is to determine the role of myeloid cell-specific NF-κB in lung tumorigenesis. In mice with myeloid cell-targeted IKKβ deletion (IKKβΔmye mice), we observed increased inflammatory mediator expression at 1 week after intraperitoneal injection of urethane (1 μg/g). At 6 weeks post-urethane injection, lungs of IKKβΔmye mice exhibited an increased atypical adenomatous hyperplastic lesion burden, which was accompanied by an increased inflammatory cell influx into the lungs of IKKβΔmye mice compared to wild-type (WT) controls. No difference in total macrophages or the proportion of M2 polarized macrophages in whole lungs was observed by flow cytometry at 6 weeks post-urethane; however, the proportion of CD11b+Gr1hi cells was increased in IKKβΔmye mice. At 4 months after urethane injection, we found an increase in lung tumor numbers (5.6±0.6 in WT, 10.0±1.5 in IKKβΔmye) and a trend towards decreased tumor size in IKKβΔmye mice compared to WT controls. IKKβΔmye mice contained significantly higher numbers of neutrophils in bronchoalveolar lavage at this time point compared to WT controls. In addition, lungs of IKKβΔmye mice exhibited more CD11b+Gr1hi cells in whole lungs as measured by flow cytometry. Our data indicate that inhibition of NF-κB signaling in myeloid cells results in a paradoxical increase in lung inflammation accompanied by enhanced urethane-induced lung tumorigenesis. We conclude that the impact of NF-κB signaling on lung tumorigenesis is cell type specific and that NF-κB activation in myeloid cells functions to limit urethane-induced inflammation and reduce tumor formation in the lungs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 529. doi:1538-7445.AM2012-529