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1.
Oncogene ; 33(10): 1239-48, 2014 Mar 06.
Article in English | MEDLINE | ID: mdl-23563178

ABSTRACT

Smoking is the most important risk factor for both lung cancer (LC) and chronic obstructive pulmonary disease. The aim of this study was to investigate the role of myeloid cell nuclear factor-κB in the regulation of tumor cell growth signaling. We subjected mice lacking myeloid RelA/p65 (rela(Δ-/-)) to a metastatic LC model. Cigarette smoke (CS) exposure significantly increased the proliferation of Lewis lung carcinoma cell tumors in wild-type mice. In CS-exposed rela(Δ-/-) mice, the tumor growth was largely inhibited. Transcriptome and pathway analysis of cancer tissue revealed a fundamental impact of myeloid cells on various growth signaling pathways, including the Wnt/ß-catenin pathway. In conclusion, myeloid RelA/p65 is necessary to link smoke-induced inflammation with LC growth and has a role in the activation of Wnt/ß-catenin signaling in tumor cells.


Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , Cell Proliferation , Lung Neoplasms/metabolism , Myeloid Cells/metabolism , Transcription Factor RelA/physiology , Wnt Signaling Pathway , Animals , Carcinoma, Lewis Lung/etiology , Carcinoma, Lewis Lung/metabolism , Carcinoma, Lewis Lung/pathology , Carcinoma, Non-Small-Cell Lung/etiology , Carcinoma, Non-Small-Cell Lung/secondary , Cell Line, Tumor , Coculture Techniques , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Lung Neoplasms/etiology , Lung Neoplasms/pathology , Macrophages, Alveolar/metabolism , Mice , Mice, Knockout , Neoplasm Transplantation , Pneumonia/etiology , Pneumonia/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Smoking/adverse effects , Transcriptome , Tumor Burden , Tumor Necrosis Factor-alpha/metabolism , beta Catenin/metabolism
2.
Oncogene ; 33(21): 2709-16, 2014 May 22.
Article in English | MEDLINE | ID: mdl-23812430

ABSTRACT

Antimicrobial peptides, such as the cathelicidin LL-37/hCAP-18 and its mouse homolog cathelicidin-related antimicrobial peptide (CRAMP), are important effectors of the innate immune system with direct anti-bacterial activity. Cathelicidin is possibly involved in the regulation of tumor cell growth. The aim of this study was to characterize the role of cathelicidin expressed in non-tumorous cells in a preclinical mouse model of tumor growth. Wild-type and CRAMP-deficient animals were exposed to cigarette smoke (CS) and Lewis lung carcinoma cells were injected to initiate the growth of tumors in the lung. CS exposure significantly increased the proliferation of lung tumors in wild-type mice, but not in CRAMP-deficient mice. CS exposure induced the recruitment of myeloid cell into tumor tissue in a CRAMP-dependent manner. Mice lacking RelA/p65 specifically in myeloid cells showed impaired recruitment of CRAMP-positive cells into the lung. In vitro studies with human cells showed that LL-37/hCAP-18 in macrophages is induced by soluble factors derived from cancer cells. Taken together, these data indicate that cathelicidin expressed from myeloid cells promotes CS-induced lung tumor growth by further recruitment of inflammatory cells. The regulation of cathelicidin expression involves myeloid p65/RelA and soluble factor from tumor cells.


Subject(s)
Carcinoma, Lewis Lung/metabolism , Cathelicidins/biosynthesis , Lung Neoplasms/metabolism , Myeloid Cells/metabolism , Animals , Antimicrobial Cationic Peptides , Carcinoma, Lewis Lung/immunology , Carcinoma, Lewis Lung/secondary , Cell Line, Tumor , Coculture Techniques , Humans , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Myeloid Cells/immunology , Neoplasm Transplantation , Smoking/adverse effects , Transcription Factor RelA/genetics , Transcription Factor RelA/metabolism , Tumor Burden
3.
Eur Respir J ; 35(2): 343-52, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19679599

ABSTRACT

The pulmonary innate immune system in the respiratory tract eliminates inhaled pathogens. Several cell types contribute to host defense within a complex network. The aim of this study was to evaluate the role of macrophages during pneumonia and in the regulation of the epithelial response to microorganisms. We performed lung infection models in mice lacking myeloid RelA/p65. To study the mechanistic relationships between individual cell types, we applied co-culture models composed of airway epithelial cells (AECs) and macrophages. Mice lacking myeloid RelA/p65 showed significantly decreased bacterial clearance, cytokine expression and neutrophil influx. In addition, the induction of epithelial keratinocyte chemoattractant expression was blunted in these animals. In vitro, AECs were largely insensitive to ligands of Toll-like receptor (TLR)2 or TLR5. Exposure to secretory products of macrophages results in an increased release of pro-inflammatory cytokines and augmented antimicrobial activity. This was associated with increased expression of TLR genes and surface expression of the proteins. Experiments with blocking antibodies showed that the effect of macrophages depends on secreted mediators, including tumour necrosis factor-alpha. In conclusion, the present data show that myeloid RelA is critical for pulmonary host defense. One important mechanism is that macrophages induce the sensitivity of AEC's to microbial patterns.


Subject(s)
Lung/immunology , Myeloid Cells/metabolism , Transcription Factor RelA/metabolism , Animals , Antimicrobial Cationic Peptides/chemistry , Asthma/immunology , Cytokines/metabolism , Disease Models, Animal , Epithelial Cells/immunology , Flow Cytometry , Lung/metabolism , Macrophages/metabolism , Mice , Neutrophils/metabolism , Pulmonary Disease, Chronic Obstructive/immunology , Toll-Like Receptors/metabolism
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