title: M. tuberculosis induction of matrix metalloproteinase-9: the role of mannose and receptor-mediated mechanisms.
abstract: Mycobacterium tuberculosis (Mtb) infection induces the expression of matrix metalloproteinase-9 (MMP-9) in mouse lungs. In cultured human monocytic cells, Mtb bacilli and the cell wall glycolipid lipoarabinomannan (LAM) stimulate high levels of MMP-9 activity. Here, we explore the cellular mechanisms involved in the induction of MMP-9 by Mtb. We show that infection of THP-1 cells with Mtb caused a fivefold increase in MMP-9 mRNA that was associated with increased MMP-9 activity. MMP-9 induction was dependent on microtubule polymerization and protein kinase activation and was associated with increased DNA binding by the transcription factor activator protein-1 (AP-1), which appeared to be important for MMP-9 expression. We then explored the surface molecules potentially involved in Mtb induction of MMP-9, focusing on ligands of the mannose and beta-glucan receptors. MMP-9 activity was induced by the mannose receptor ligands mannan, zymosan, and LAM, whereas the beta-glucan receptor ligand laminarin was not effective. The most active inducers of MMP-9 activity were the particulate ligand zymosan and LAM. Pretreatment of cells with an anti-mannose receptor monoclonal antibody, but not anti-complement receptor 3, decreased the induction of MMP-9 activity by Mtb bacilli. Together, these results suggest that MMP-9 induction by Mtb occurs by receptor-mediated signaling mechanisms involving the binding of mannosylated ligands to mannose receptors, the modulation by cytoskeletal elements such as microtubules, the activation of protein kinases, and transcriptional activation by AP-1.
authors.affiliation: Pulmonary and Critical Care Division, Department of Medicine, Atlanta Veterans Affairs Medical Center and Emory University School of Medicine, Atlanta, Georgia 30033, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Rivera-Marrero
authors.forename: William
authors.initials: W
authors.lastname: Schuyler
authors.forename: Susanne
authors.initials: S
authors.lastname: Roser
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Ritzenthaler
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Newburn
authors.forename: Jesse
authors.initials: J
authors.lastname: Roman
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002460:Cell Line; D003599:Cytoskeleton / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D004790:Enzyme Induction / Q000502:physiology; D006801:Humans; D037181:Lectins, C-Type; D008024:Ligands; D016177:Macrophage-1 Antigen / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008358:Mannose / Q000502:physiology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011134:Polysaccharides / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology; D014376:Tuberculosis / Q000201:enzymology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D037181:Lectins, C-Type; D008024:Ligands; D016177:Macrophage-1 Antigen; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011134:Polysaccharides; D011956:Receptors, Cell Surface; D018808:Transcription Factor AP-1; D011494:Protein Kinases; D020780:Matrix Metalloproteinase 9; D008358:Mannose