Transcriptional Mechanisms Regulating Alveolar Epithelial Cell-specific CCL5 Secretion in Pulmonary Tuberculosis

CCL5 (or RANTES (regulated upon activation, normal T cell expressed and secreted)) recruits T lymphocytes and monocytes. The source and regulation of CCL5 in pulmonary tuberculosis are unclear. Infection of the human alveolar epithelial cell line (A549) by Mycobacterium tuberculosis caused no CCL5 secretion and little monocyte secretion. Conditioned medium from tuberculosis-infected human monocytes (CoMTB) stimulated significant CCL5 secretion from A549 cells and from primary alveolar, but not upper airway, epithelial cells. Differential responsiveness of small airway and normal human bronchial epithelial cells to CoMTB but not to conditioned medium from unstimulated human monocytes was specific to CCL5 and not to CXCL8. CoMTB induced CCL5 mRNA accumulation in A549 cells and induced nuclear translocation of nuclear factor κB (NFκB) subunits p50, p65, and c-rel at 1 h; nuclear binding of activator protein (AP)-1 (c-Fos, FosB, and c-Jun) at 4–8 h; and binding of NF-interleukin (IL)-6 at 24 h. CCL5 promoter-reporter analysis using deletion and site-specific mutagenesis constructs demonstrated a key role for AP-1, NF-IL-6, and NFκB in driving CoMTB-induced promoter activity. The IL-1 receptor antagonist inhibited A549 and small airway epithelial cell CCL5 secretion, gene expression, and promoter activity. CoMTB contained IL-1β, and recombinant IL-1β reproduced CoMTB effects. Monocyte alveolar, but not upper airway, epithelial cell networks in pulmonary tuberculosis cause AP-1-, NF-IL-6-, and NFκB-dependent CCL5 secretion. IL-1β is the critical regulator of tuberculosis-stimulated CCL5 secretion in the lung. CCL5 (or RANTES (regulated upon activation, normal T cell expressed and secreted)) recruits T lymphocytes and monocytes. The source and regulation of CCL5 in pulmonary tuberculosis are unclear. Infection of the human alveolar epithelial cell line (A549) by Mycobacterium tuberculosis caused no CCL5 secretion and little monocyte secretion. Conditioned medium from tuberculosis-infected human monocytes (CoMTB) stimulated significant CCL5 secretion from A549 cells and from primary alveolar, but not upper airway, epithelial cells. Differential responsiveness of small airway and normal human bronchial epithelial cells to CoMTB but not to conditioned medium from unstimulated human monocytes was specific to CCL5 and not to CXCL8. CoMTB induced CCL5 mRNA accumulation in A549 cells and induced nuclear translocation of nuclear factor κB (NFκB) subunits p50, p65, and c-rel at 1 h; nuclear binding of activator protein (AP)-1 (c-Fos, FosB, and c-Jun) at 4–8 h; and binding of NF-interleukin (IL)-6 at 24 h. CCL5 promoter-reporter analysis using deletion and site-specific mutagenesis constructs demonstrated a key role for AP-1, NF-IL-6, and NFκB in driving CoMTB-induced promoter activity. The IL-1 receptor antagonist inhibited A549 and small airway epithelial cell CCL5 secretion, gene expression, and promoter activity. CoMTB contained IL-1β, and recombinant IL-1β reproduced CoMTB effects. Monocyte alveolar, but not upper airway, epithelial cell networks in pulmonary tuberculosis cause AP-1-, NF-IL-6-, and NFκB-dependent CCL5 secretion. IL-1β is the critical regulator of tuberculosis-stimulated CCL5 secretion in the lung. CCL5 1The abbreviations used are: CCL, CC chemokine ligand; BALF, bronchoalveolar lavage fluid; RSV, respiratory syncytial virus; CXCL, CXC chemokine ligand; IL, interleukin; ra, receptor antagonist; AP, activator protein; NF, nuclear factor; SAEC, small airway epithelial cells; NHBE, normal human bronchial epithelial cells; MOI, multiplicity of infection; CoMTB, conditioned medium from M. tuberculosis-infected human monocytes; CoMControl, conditioned medium from unstimulated human monocytes; TNF, tumor necrosis factor; ELISA, enzyme-linked immunosorbent assay; TPA, triphorbol acetate; EMSA, electrophoretic mobility shift assay; TRE, triphorbol acetate-response element; WT, wild type.1The abbreviations used are: CCL, CC chemokine ligand; BALF, bronchoalveolar lavage fluid; RSV, respiratory syncytial virus; CXCL, CXC chemokine ligand; IL, interleukin; ra, receptor antagonist; AP, activator protein; NF, nuclear factor; SAEC, small airway epithelial cells; NHBE, normal human bronchial epithelial cells; MOI, multiplicity of infection; CoMTB, conditioned medium from M. tuberculosis-infected human monocytes; CoMControl, conditioned medium from unstimulated human monocytes; TNF, tumor necrosis factor; ELISA, enzyme-linked immunosorbent assay; TPA, triphorbol acetate; EMSA, electrophoretic mobility shift assay; TRE, triphorbol acetate-response element; WT, wild type. is a member of the CC chemokine subfamily and a chemoattractant for CD4+ memory T lymphocytes, monocytes, and eosinophils (1Schall T.J. 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