Journal Article

Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFα, NFκB, p38 and caspase 8 dependent pathways

Green, Justin A, Ong, Catherine WM, Elkington, Paul T, Dholakia, Shruti, Friedland, Jon S, Janczar, Karolina, Moores, Rachel, Roncaroli, Federico, Fry, Julie

2011

Overview

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.

• Publisher: BioMed Central,BMC
• Subject: Anti-Inflammatory Agents, Non-Steroidal - metabolism / Biomedical and Life Sciences / Biomedicine / Caspase 8 - metabolism / Culture Media, Conditioned - chemistry / Extracellular Signal-Regulated MAP Kinases - metabolism / Humans / Immunology / Matrix Metalloproteinase 2 - genetics / Matrix Metalloproteinase 2 - metabolism / Microglia - cytology / Microglia - metabolism / Monocytes - cytology / Monocytes - metabolism / Monocytes - microbiology / Mycobacterium / Mycobacterium tuberculosis - metabolism / Mycobacterium tuberculosis - pathogenicity / Neurobiology / Neurology / Neurosciences / NF-kappa B - metabolism / p38 Mitogen-Activated Protein Kinases - metabolism / Sesquiterpenes - metabolism / Sesquiterpenes, Guaiane / Signal Transduction - physiology / Tuberculosis, Central Nervous System - metabolism / Tuberculosis, Central Nervous System - microbiology / Tumor Necrosis Factor-alpha - metabolism