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), 5865-5872. (doi:10.4049/​jimmunol.0801935). (PMID:19380835).

Download

[img] PDF
Restricted to internal admin

Download (1289Kb)

Description/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.

Item Type: Article
Digital Object Identifier (DOI): doi:10.4049/​jimmunol.0801935
ISSNs: 0022-1767 (print)
1550-6606 (electronic)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RC Internal medicine
Divisions: Faculty of Medicine
ePrint ID: 341055
Date Deposited: 12 Jul 2012 09:11
Last Modified: 27 Mar 2014 20:23
URI: http://eprints.soton.ac.uk/id/eprint/341055

Actions (login required)

View Item View Item

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics