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

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.

• Authors: Lucinda Rand, Justin A Green, Luísa Saraiva, Jon S Friedland, Paul T G Elkington
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 182 Issue 9 Pg. 5865-72 (May 01 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 19380835 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antitubercular Agents
• Matrix Metalloproteinase Inhibitors
• Aminosalicylic Acid
• p38 Mitogen-Activated Protein Kinases
• MMP7 protein, human
• Matrix Metalloproteinase 7
• MMP1 protein, human
• Matrix Metalloproteinase 1
• Dinoprostone

Topics

• Aminosalicylic Acid (pharmacology)
• Antitubercular Agents (pharmacology)
• Cells, Cultured
• Dinoprostone (antagonists & inhibitors, metabolism, physiology)
• Gene Expression Regulation, Bacterial (drug effects, immunology)
• Humans
• Macrophages (enzymology, metabolism, microbiology)
• Matrix Metalloproteinase 1 (genetics, metabolism)
• Matrix Metalloproteinase 7 (genetics, metabolism)
• Matrix Metalloproteinase Inhibitors
• Mycobacterium tuberculosis (drug effects, growth & development, immunology)
• Phosphorylation (drug effects, immunology)
• Signal Transduction (drug effects, immunology)
• Tuberculosis, Pulmonary (drug therapy, enzymology, immunology)
• p38 Mitogen-Activated Protein Kinases (metabolism, physiology)