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Published ahead of print on June 15, 2007, doi:10.1165/rcmb.2007-0011OC

Am. J. Respir. Cell Mol. Biol., Volume 37, Number 4, October 2007, 431-437

A more recent version of this article appeared on October 1, 2007
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Submitted on January 17, 2007
Revised on June 14, 2007

Synergistic Up-regulation of Epithelial Cell Matrix Metalloproteinase-9 Secretion in Tuberculosis

Paul T Elkington1, Justin A Green1, Jenny E Emerson1, Laura D Lopez-Pascua1, Joseph J Boyle2, Cecilia M O'Kane1, and Jon S Friedland1*

1 Department of Infectious Diseases and Immunity, Imperial College London, Hammersmith Campus, London, United Kingdom, 2 Department of Histopathology, Imperial College London, Hammersmith Campus, London, United Kingdom

* To whom correspondence should be addressed. E-mail: j.friedland{at}imperial.ac.uk.

Mycobacterium tuberculosis (MTb) kills approximately 2 million people each year. MTb must drive host tissue destruction to disseminate and also to cause pulmonary cavitation. Matrix metalloproteinase-9 (MMP-9, gelatinase B) is implicated in this Tb-related immunopathology. We demonstrate that conditioned media from MTb-infected monocytes (CoMTb) but not direct infection with MTb up-regulates MMP-9 gene expression and secretion from primary human bronchial epithelial cells (NHBE). MMP-9 secretion was increased 8.7-fold by CoMTb (p<0.05) as assayed by gelatin zymography. A549 and 16HBE14o epithelial cell MMP secretion was significantly less than primary NHBE secretion. MMP-9 secretion was decreased 53.2% by inhibition of the p38 MAPK by SB203580 (p<0.01) and 48.3% by inhibition of ERK with PD98059 (p<0.05). MMP-9 secretion was prostaglandin-independent. TNF-{alpha} was necessary but not sufficient for MMP-9 up-regulation by the monocyte-epithelial cell network. Soluble factors derived from Tb culture synergized with TNF-{alpha} to increase MMP-9 secretion by NHBE 6-fold (p<0.01 compared to either stimulus alone). Together these data reveal a new mechanism by which host- and pathogen-derived factors act together in MTb infection to drive MAPK-dependent MMP-9 secretion from respiratory epithelial cells.




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