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J. Biol. Chem., Vol. 279, Issue 26, 27199-27210, June 25, 2004

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

Melissa I. Wickremasinghe, Lynette H. Thomas, Cecilia M. O'Kane, Jasim Uddin, and Jon S. Friedland

From the Department of Infectious Diseases, Imperial College, Hammersmith Campus, London W12 0NN, United Kingdom

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 B (NFB) 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 NFB 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-1, and recombinant IL-1 reproduced CoMTB effects. Monocyte alveolar, but not upper airway, epithelial cell networks in pulmonary tuberculosis cause AP-1-, NF-IL-6-, and NFB-dependent CCL5 secretion. IL-1 is the critical regulator of tuberculosis-stimulated CCL5 secretion in the lung.

Received for publication, March 19, 2004 , and in revised form, April 23, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Infectious Diseases, Imperial College, Hammersmith Hospital, Du Cane Rd., London W12 0NN, England. Tel.: 44-20-8383-8521; Fax: 44-20-8383-3394; E-mail: j.friedland{at}ic.ac.uk.

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