Abstract
Leukocyte-derived matrix metalloproteinases (MMP) are implicated in the tissue destruction characteristic of tuberculosis (TB). The contribution of lung stromal cells to MMP activity in TB is unknown. Oncostatin M (OSM) is an important stimulus to extrapulmonary stromal MMP induction, but its role in regulation of pulmonary MMP secretion or pathophysiology of TB is unknown. We investigated OSM secretion from Mycobacterium tuberculosis (Mtb)-infected human monocytes/macrophages and the networking effects of such OSM on lung fibroblast MMP secretion. Mtb increased monocyte OSM secretion dose dependently in vitro. In vivo tuberculous granulomas immunostained positively for OSM. Further, conditioned media from Mtb-infected monocytes (CoMTb) induced monocyte OSM secretion (670 +/- 55 versus 166 +/- 14 pg/mL in controls), implicating an autocrine loop. Mtb-induced OSM secretion was prostaglandin (PG) sensitive, and required activation of surface G-protein coupled receptors. OSM induction was ERK MAP kinase dependent, p38-requiring but JNK-independent. OSM synergized with TNF-alpha, a key cytokine in TB granuloma formation, to stimulate pulmonary fibroblast MMP-1/-3 secretion, while suppressing secretion of tissue inhibitors of metalloproteinases-1/-2. In summary, Mtb infection of monocytes results in PG-dependent OSM secretion, which synergizes with TNF-alpha to drive functionally unopposed fibroblast MMP-1/-3 secretion, demonstrating a previously unrecognized role for OSM in TB.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Bucladesine / pharmacology
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Cell Line
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Cholera Toxin / pharmacology
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Culture Media, Conditioned / pharmacology
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism*
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Humans
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Indomethacin / pharmacology
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Lung / cytology
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Macrophages / metabolism
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Macrophages / microbiology
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Matrix Metalloproteinase 1 / metabolism
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Matrix Metalloproteinase 3 / metabolism
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Matrix Metalloproteinases, Secreted / metabolism*
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Monocytes / drug effects
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Monocytes / metabolism
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Monocytes / microbiology*
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Oncostatin M / metabolism*
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Oncostatin M / pharmacology
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Pertussis Toxin / pharmacology
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Phosphorylation / drug effects
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Prostaglandins / metabolism
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Receptors, G-Protein-Coupled / agonists
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Receptors, G-Protein-Coupled / metabolism
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Tissue Inhibitor of Metalloproteinase-1 / metabolism
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Tissue Inhibitor of Metalloproteinase-2 / metabolism
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Tuberculoma / metabolism
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Tuberculoma / pathology
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Tuberculosis, Pleural / metabolism*
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Tuberculosis, Pleural / pathology
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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Culture Media, Conditioned
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Prostaglandins
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Receptors, G-Protein-Coupled
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Tissue Inhibitor of Metalloproteinase-1
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Tumor Necrosis Factor-alpha
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Oncostatin M
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Tissue Inhibitor of Metalloproteinase-2
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Bucladesine
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Cholera Toxin
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Pertussis Toxin
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Extracellular Signal-Regulated MAP Kinases
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Matrix Metalloproteinases, Secreted
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Matrix Metalloproteinase 3
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Matrix Metalloproteinase 1
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Indomethacin