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

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

Correspondence and requests for reprints should be addressed to Professor J. S. Friedland, Department of Infectious Diseases, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. 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 mitogen-activated protein kinase (MAPK) by SB203580 (P < 0.01) and 48.3% by inhibition of extracellular signal–regulated kinase with PD98059 (P < 0.05). MMP-9 secretion was prostaglandin independent. TNF- 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- to increase MMP-9 secretion by NHBE 6-fold (P < 0.01 compared with 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.

Key Words: tuberculosis • matrix metalloproteinase • epithelial cell

CLINICAL RELEVANCE We show that pulmonary epithelial cells may be a key source of matrix metalloproteinase-9 (MMP-9) in tuberculosis. We identify a novel network up-regulating MMP secretion, with results also relevant to other pulmonary pathologies.