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Mycobacterium tuberculosis up-regulates matrix metalloproteinase-1 secretion from human airway epithelial cells via a p38 MAPK switch

Elkington, Paul T.G., Emerson, Jenny E., Lopez-Pascua, Laura D. C., O'Kane, Cecilia M., Horncastle, Donna E., Boyle, Joseph J. and Friedland, Jon S. (2005) Mycobacterium tuberculosis up-regulates matrix metalloproteinase-1 secretion from human airway epithelial cells via a p38 MAPK switch Journal of Immunology, 175, (8), pp. 5333-5340. (PMID:16210639).

Record type: Article


Pulmonary cavitation is vital to the persistence and spread of Mycobacterium tuberculosis (MTb), but mechanisms underlying this lung destruction are poorly understood. Fibrillar type I collagen provides the lung's tensile strength, and only matrix metalloproteinases (MMPs) can degrade it at neutral pH. We investigated MTb-infected lung tissue and found that airway epithelial cells adjacent to tuberculosis (Tb) granulomas expressed a high level of MMP-1 (interstitial collagenase). Conditioned media from MTb-infected monocytes (CoMTb) up-regulated epithelial cell MMP-1 promoter activity, gene expression, and secretion, whereas direct MTb infection did not. CoMTb concurrently suppressed tissue inhibitor of metalloprotease-1 (TIMP-1) secretion, further promoting matrix degradation, and in Tb patients very low TIMP-1 expression was detected. MMP-1 up-regulation required synergy between TNF-alpha and G protein-coupled receptor signaling pathways. CoMTb stimulated p38 MAPK phosphorylation, and this is the point of TNF-alpha synergy with G protein-coupled receptor activation. Furthermore, p38 phosphorylation was the switch up-regulating MMP-1 activity and decreasing TIMP-1 secretion. Activated p38 localized to MMP-1-secreting airway epithelial cells in Tb patients. These data reveal a monocyte-epithelial cell network whereby MTb may drive tissue destruction, and they demonstrate that p38 phosphorylation is a key regulatory point in the generation of a matrix-degrading phenotype.

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Published date: 15 October 2005
Organisations: Faculty of Medicine


Local EPrints ID: 341070
ISSN: 0022-1767
PURE UUID: f4b7ab27-4c8f-4072-8a3e-024448202a19
ORCID for Paul T.G. Elkington: ORCID iD

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Date deposited: 12 Jul 2012 12:55
Last modified: 18 Jul 2017 05:39

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Author: Jenny E. Emerson
Author: Laura D. C. Lopez-Pascua
Author: Cecilia M. O'Kane
Author: Donna E. Horncastle
Author: Joseph J. Boyle
Author: Jon S. Friedland

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