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Published ahead of print on September 1, 2005, doi:10.1164/rccm.200505-753OC

Am. J. Respir. Crit. Care Med., Volume 172, Number 12, December 2005, 1596-1604

A more recent version of this article appeared on December 15, 2005
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Submitted on May 13, 2005
Accepted on August 26, 2005

Mycobacterium tuberculosis but not vaccine BCG specifically up-regulates matrix metalloproteinase-1

Paul TG Elkington1, Robert K Nuttall2, Joseph J Boyle3, Cecilia M O'Kane1, Donna E Horncastle3, Dylan R Edwards2, and Jon S Friedland1*

1 Department of Infectious Diseases, Imperial College, Hammersmith Campus, London, United Kingdom, 2 School of Biological Sciences, University of East Anglia, Norwich, United Kingdom, 3 Department of Histopathology, Imperial College, Hammersmith Campus, London, United Kingdom

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

Rationale: Pulmonary cavitation is fundamental to the global success of Mycobacterium tuberculosis. However, the mechanisms of this lung destruction are poorly understood. The biochemistry of lung matrix predicts matrix metalloproteinase involvement in immunopathology. Methods: We investigated gene expression of all matrix metalloproteinases, ADAMs (a disintegrin and metalloproteinase) and tissue inhibitors of metalloproteinases in M. tuberculosis-infected human macrophages by Real Time PCR. Matrix metalloproteinase secretion was measured by zymography and Western analysis, and expression in patients with pulmonary tuberculosis was localized by immunohistochemistry. Results: MMP-1 and MMP-7 gene expression and secretion are potently up-regulated by M. tuberculosis, and no increase in tissue inhibitor of metalloproteinase expression occurs to oppose their activity. Dexamethasone completely suppresses MMP-1 but not MMP-7 gene expression and secretion. In patients with active tuberculosis, macrophages express MMP-1 and MMP-7 adjacent to areas of tissue destruction. MMP-1 but not MMP-7 expression and secretion is relatively M. tuberculosis-specific, is not up-regulated by tuberculosis-associated cytokines and is prostaglandin dependent. In contrast, the vaccine M.bovis BCG does not stimulate MMP-1 secretion from human macrophages, although M. tuberculosis and BCG do up-regulate MMP-7 equally. BCG-infected macrophages secrete reduced prostaglandin E2 concentrations compared to M. tuberculosis-infected macrophages, and prostaglandin pathway supplementation augments MMP-1 secretion from BCG-infected cells. Conclusions: M. tuberculosis specifically up-regulates MMP-1 in a cellular model of human infection and in patients with tuberculosis. In contrast, vaccine BCG, which does not cause lung cavitation, does not up-regulate prostaglandin E2-dependent MMP-1 secretion.
Key words: Mycobacterium tuberculosis, Matrix metalloproteinases, Macrophage, Prostaglandin E, Pathology




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