title: 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.affiliation: Department of Infectious Diseases and Immunity, Imperial College London, Hammersmith Campus, London, United Kingdom.
authors.forename: Lucinda
authors.initials: L
authors.lastname: Rand
authors.forename: Justin A
authors.initials: JA
authors.lastname: Green
authors.forename: Luísa
authors.initials: L
authors.lastname: Saraiva
authors.forename: Jon S
authors.initials: JS
authors.lastname: Friedland
authors.forename: Paul T G
authors.initials: PT
authors.lastname: Elkington
mesh_terms: D010131:Aminosalicylic Acid / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology; D002478:Cells, Cultured; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*
chemical_list: D000995:Antitubercular Agents; D061965:Matrix Metalloproteinase Inhibitors; D010131:Aminosalicylic Acid; D048051:p38 Mitogen-Activated Protein Kinases; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone