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- Title
Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFα, NFκB, p38 and caspase 8 dependent pathways.
- Authors
Green, Justin A.; Dholakia, Shruti; Janczar, Karolina; Ong, Catherine W. M.; Moores, Rachel; Fry, Julie; Elkington, Paul T.; Roncaroli, Federico; Friedland, Jon S.; Ong, Catherine Wm
- 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.
- Subjects
NEUROLOGICAL research; MYCOBACTERIAL diseases; MYCOBACTERIUM tuberculosis; CENTRAL nervous system; INFLAMMATORY mediators; GENETIC regulation; CELL metabolism; PROTEIN metabolism; TUBERCULOSIS microbiology; HYDROCARBON metabolism; CELLS; CELLULAR signal transduction; COMPARATIVE studies; CULTURE media (Biology); RESEARCH methodology; MEDICAL cooperation; MONOCYTES; NONSTEROIDAL anti-inflammatory agents; PROTEOLYTIC enzymes; RESEARCH; TRANSFERASES; TUBERCULOSIS; TUMOR necrosis factors; DNA-binding proteins; EVALUATION research
- Publication
Journal of Neuroinflammation, 2011, Vol 8, Issue 1, p46
- ISSN
1742-2094
- Publication type
journal article
- DOI
10.1186/1742-2094-8-46