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Matrix metalloproteinase-1 is regulated in tuberculosis by a p38 MAPK-dependent, p-aminosalicylic acid-sensitive signaling cascade

Rand, Lucinda, Green, Justin A., Saraiva, Luísa, Friedland, Jon S. and Elkington, Paul T.G. (2009) Matrix metalloproteinase-1 is regulated in tuberculosis by a p38 MAPK-dependent, p-aminosalicylic acid-sensitive signaling cascade Journal of Immunology, 182, (9), pp. 5865-5872. (doi:10.4049/?jimmunol.0801935). (PMID:19380835).

Record type: Article

Abstract

Mycobacterium tuberculosis (M. tb) must cause lung disease to spread. Matrix metalloproteinases (MMPs) degrade the extracellular matrix and are implicated in tuberculosis-driven tissue destruction. We investigated signaling pathways regulating macrophage MMP-1 and -7 in human pulmonary tuberculosis and examine the hypothesis that the antimycobacterial drug p-aminosalicylic acid acts by inhibiting such pathways. In primary human macrophages, M. tb up-regulates gene expression and secretion of MMP-1 (interstitial collagenase) and MMP-7 (matrilysin). In tuberculosis patients, immunohistochemical analysis of lung biopsies demonstrates that p38 MAPK is phosphorylated in macrophages surrounding granulomas. In vitro, M. tb drives p38 phosphorylation. p38 inhibition suppresses M. tb-dependent MMP-1 secretion by 57.8% and concurrently increases secretion of its specific inhibitor TIMP-1 by 243.7%, demonstrating that p38 activity regulates matrix degradation by macrophages. p38 signals downstream to the cyclooxygenase 2/PGE(2) pathway. p-Aminosalicyclic acid, an agent used to treat drug-resistant tuberculosis, inhibits M. tb-driven MMP-1 but not MMP-7 gene expression and secretion. PAS acts by blocking PGE(2) production without affecting M. tb growth. In summary, p-aminosalicyclic acid decreases MMP-1 activity by inhibiting a p38 MAPK-PG signaling cascade, suggesting that this pathway is a therapeutic target to reduce inflammatory tissue destruction in tuberculosis.

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Published date: 1 May 2009
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 341055
URI: http://eprints.soton.ac.uk/id/eprint/341055
ISSN: 0022-1767
PURE UUID: 19abdf65-100a-4b74-97d1-51570c1b96e9
ORCID for Paul T.G. Elkington: ORCID iD orcid.org/0000-0003-0390-0613

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Date deposited: 12 Jul 2012 09:11
Last modified: 18 Jul 2017 05:39

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Contributors

Author: Lucinda Rand
Author: Justin A. Green
Author: Luísa Saraiva
Author: Jon S. Friedland

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