Pulmonary epithelial cells are a source of IL-8 in the response to Mycobacterium tuberculosis: essential role of IL-1 from infected monocytes in a NF-kappa B-dependent network

M I Wickremasinghe, L H Thomas, J S Friedland
Journal of Immunology 1999 October 1, 163 (7): 3936-47
Pulmonary epithelial cells, covering a 70-m2 surface area, have not previously been considered an important source of chemokines in pulmonary tuberculosis. We analyzed IL-8 secretion from A549 cells and primary normal human bronchial epithelial cells (NHBE) infected by Mycobacterium tuberculosis. Direct infection of A549 cells by M. tuberculosis caused IL-8 secretion of 7720 +/- 1610 pg/106 cells, but no IL-8 secretion from NHBE after 24 h. In contrast, conditioned media from M. tuberculosis-infected human monocytes (CoMTB) induced a much greater IL-8 secretion of 92,635 +/- 13,180 pg/106 A549 cells and 13,416 +/- 3,529 pg/106 NHBE after 24 h. CoMTB induced rapid IL-8 mRNA accumulation, which was stable over 24 h, compared with TNF-alpha-induced transcripts. CoMTB stimulated nuclear binding of p65, p50, and c-Rel subunits of NF-kappa B to IL-8 promoter sequences. Transient transfections with IL-8 promoter reporter constructs showed NF-kappa B binding-site mutations abolished IL-8 promoter activity while NF-IL-6 binding-site mutations decreased promoter activity to 50.2 +/- 6.3% of wild-type activity. IL-1R antagonist but not neutralizing anti-TNF-alpha inhibited epithelial cell IL-8 secretion, mRNA accumulation, and NF-kappa B binding. Recombinant IL-1 beta (2 ng/ml) induced similar levels of IL-8 secretion to CoMTB in both A549 cells and NHBE. Pulmonary epithelial cells are a major source of IL-8 in the initial host response to pulmonary tuberculosis. Such IL-8 secretion is NF-kappa B dependent, NF-IL-6 requiring, and activated by an IL-1-mediated pathway as a consequence of phagocytosis of M. tuberculosis by monocytes.

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