Matrix metalloproteinase-1 is regulated in tuberculosis by a p38 MAPK-dependent, p-aminosalicylic acid-sensitive signaling cascade
Matrix metalloproteinase-1 is regulated in tuberculosis by a p38 MAPK-dependent, p-aminosalicylic acid-sensitive signaling cascade
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.
5865-5872
Rand, Lucinda
0a53e76e-e467-4db7-8d55-7225dc4fc961
Green, Justin A.
9c179973-04b4-48cb-a685-1078e3ab13cd
Saraiva, Luísa
b8d2793b-3acd-4c13-95cc-ed9f4621b66d
Friedland, Jon S.
9968669f-afe0-4163-9b35-3b476246fd4a
Elkington, Paul T.G.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
1 May 2009
Rand, Lucinda
0a53e76e-e467-4db7-8d55-7225dc4fc961
Green, Justin A.
9c179973-04b4-48cb-a685-1078e3ab13cd
Saraiva, Luísa
b8d2793b-3acd-4c13-95cc-ed9f4621b66d
Friedland, Jon S.
9968669f-afe0-4163-9b35-3b476246fd4a
Elkington, Paul T.G.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
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), .
(doi:10.4049/?jimmunol.0801935).
(PMID:19380835)
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
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Local EPrints ID: 341055
URI: http://eprints.soton.ac.uk/id/eprint/341055
ISSN: 0022-1767
PURE UUID: 19abdf65-100a-4b74-97d1-51570c1b96e9
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Date deposited: 12 Jul 2012 09:11
Last modified: 15 Mar 2024 03:43
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Author:
Lucinda Rand
Author:
Justin A. Green
Author:
Luísa Saraiva
Author:
Jon S. Friedland
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