Monocyte-dependent oncostatin M and TNF-α synergize to stimulate unopposed matrix metalloproteinase-1/3 secretion from human lung fibroblasts in tuberculosis

Department of Infectious Diseases and Immunity, Imperial College London, London, UK.
European Journal of Immunology (Impact Factor: 4.03). 06/2008; 38(5):1321-30. DOI: 10.1002/eji.200737855
Source: PubMed


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.

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    • "In this study, we demonstrated that a TNF-dependent cytokine network involving M.tb-infected monocytes, but not direct infection by M.tb, down-regulates MMP-2 secretion from microglial cells via p38 MAP kinase, NFκB and caspase 8 pathways. Since M.tb infection and TNF-α usually drive gene expression and secretion of other MMPs, such as MMP-1, -3 and -9, leading to pro-inflammatory damage this was an unexpected, paradoxical finding [33,37,42]. Specifically this was the only down-regulated molecule when studying all MMPs in this model system in our previously published work and in particular contrast to the other gelatinase MMP-9 [33]. "
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    ABSTRACT: Tuberculosis (TB) of the central nervous system (CNS) is a deadly disease characterized by extensive tissue destruction, driven by molecules such as Matrix Metalloproteinase-2 (MMP-2) which targets CNS-specific substrates. In a simplified cellular model of CNS TB, we demonstrated that conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb), but not direct infection, unexpectedly down-regulates constitutive microglial MMP-2 gene expression and secretion by 72.8% at 24 hours, sustained up to 96 hours (P < 0.01), dependent upon TNF-α. In human CNS TB brain biopsies but not controls the p38 pathway was activated in microglia/macrophages. Inhibition of the p38 MAP kinase pathway resulted in a 228% increase in MMP-2 secretion (P < 0.01). In contrast ERK MAP kinase inhibition further decreased MMP-2 secretion by 76.6% (P < 0.05). Inhibition of the NFκB pathway resulted in 301% higher MMP-2 secretion than CoMTb alone (P < 0.01). Caspase 8 restored MMP-2 secretion to basal levels. However, this caspase-dependent regulation of MMP-2 was independent of p38 and NFκB pathways; p38 phosphorylation was increased and p50/p65 NFκB nuclear trafficking unaffected by caspase 8 inhibition. In summary, suppression of microglial MMP-2 secretion by M.tb-infected monocyte-dependent networks paradoxically involves the pro-inflammatory mediators TNF-α, p38 MAP kinase and NFκB in addition to a novel caspase 8-dependent pathway.
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    • "During the early stages of human tuberculosis, MTB induces an immune response [2] and subsequently leads to the development of lung granulomas consisting of macrophages, T cells, B cells, and fibroblasts [3]. Recent researches reveal that fibroblasts are not only essential in secreting chemokine for modulating inflammatory response to MTB infection and influencing the survival of MTB within macrophages [4] but also involved in the regulation of granuloma formation during MTB infection [4, 5]. Despite the potentially vital role of fibroblasts in MTB infection, the detailed MTB-regulated mechanism in fibroblasts, especially its relationship to MTB secreted protein, remains unknown. "
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