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Published ahead of print on September 1, 2005, doi:10.1164/rccm.200505-753OC
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American Journal of Respiratory and Critical Care Medicine Vol 172. pp. 1596-1604, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200505-753OC

Original Article

Mycobacterium tuberculosis, but Not Vaccine BCG, Specifically Upregulates Matrix Metalloproteinase-1

Paul T. G. Elkington*, Robert K. Nuttall*, Joseph J. Boyle, Cecilia M. O'Kane, Donna E. Horncastle, Dylan R. Edwards and Jon S. Friedland

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

Correspondence and requests for reprints should be addressed to J. S. Friedland, Ph.D., Department of Infectious Diseases, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. 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 (MMP) involvement in immunopathology.

Methods: We investigated gene expression of all MMPs, proteins with a disintegrin and metalloproteinase domain, and tissue inhibitors of metalloproteinases in M. tuberculosis–infected human macrophages by real-time polymerase chain reaction. MMP 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 upregulated 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 are relatively M. tuberculosis specific, are not upregulated by tuberculosis- associated cytokines, and are prostaglandin dependent. In contrast, the vaccine M. bovis bacillus Calmette-Guérin (BCG) does not stimulate MMP-1 secretion from human macrophages, although M. tuberculosis and BCG do upregulate MMP-7 equally. BCG-infected macrophages secrete reduced prostaglandin E2 concentrations compared with M. tuberculosis–infected macrophages, and prostaglandin pathway supplementation augments MMP-1 secretion from BCG-infected cells.

Conclusions: M. tuberculosis specifically upregulates 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 upregulate prostaglandin E2–dependent MMP-1 secretion.

Key Words: macrophage • matrix metalloproteinases • Mycobacterium tuberculosis • pathology • prostaglandin E




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