期刊
JOURNAL OF IMMUNOLOGY
卷 182, 期 9, 页码 5865-5872出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0801935
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- National Institute for Health Research
- Medical Research Council (U.K.)
- Hammersmith Hospitals Trustees
- National Institute for Health Research Biomedical Research Centre funding scheme at Imperial College
- MRC [G0500385] Funding Source: UKRI
- Medical Research Council [G0500385] Funding Source: researchfish
- National Institute for Health Research [DHCS/06/05/012] Funding Source: researchfish
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 NIMP-l activity by inhibiting a p38 MAPK-PG signaling cascade, suggesting that this pathway is a therapeutic target to reduce inflammatory tissue destruction in tuberculosis. The Journal of Immunology, 2009, 182: 5865-5872.
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