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In this study, we report evidences that Mycobacterium tuberculosis (MTB)-induced apoptosis in macrophages is reduced by a broad-spectrum hydroxamic acid-based matrix metalloproteinase (MMP) inhibitor, Batimastat (BB-94). In particular, we show that BB-94 administration to MTB-infected macrophages inhibits apoptosis and the downmodulation of membrane CD14 expression. Moreover, the addition of broad spectrum matrix metalloproteinase inhibitor to cell culture, during MTB infection, decreases the release of soluble TNF-α and leads to a simultaneous increase of membrane TNF-α. These results show that MTB-induced apoptosis in macrophages is reduced by a MMP inhibitor and most probably is related to TNF-α release. This identifies BB-94 as a simultaneous anti-apoptotic and anti-inflammatory molecule during MTB infection. [Copyright &y& Elsevier]

Examines the intracellular mycobacterial viability of mycobacterium tuberculosis (MTB)-induced apoptosis in monocytes. Association of MTB- induces apoptosis with CD14 expression; Correlation between MTB high doses and parasite survival; Role of monocytes on cytokines and chemokines release.

Mycobacterium tuberculosis (MTB) can induce apoptosis in monocytes/macrophages both in vitro and in vivo, and this phenomenon is associated with mycobacterial survival. The present study addresses the possibility that apoptotic and inflammatory pathways could coexist through a caspase-l-mediated mechanism. In this context, a caspase-1 inhibitor (YVAD), but not caspase-3 (DEVD) or caspase-4 (LEVD) inhibitors, was able to strongly inhibit MTBinduced apoptosis. Moreover, caspase-1 activity was confirmed by the increased maturation of interleukin (IL)-1β. Of interest, IL-1β and tumor necrosis factor (TNF)-α were produced massively in the course of infection, and both were inhibited by YVAD pretreatment. To determine whether TNF-α was produced actively by apoptotic cells, the intracytoplasmatic cytokine content and apoptotic phenotype were analyzed at the single-cell level. Results showed a progressive increase of TNF-α production in annexin V-positive cells. These results indicate that MTB-induced apoptosis is associated with proinflammatory cytokine production. [ABSTRACT FROM AUTHOR]

Abstract: Lysophosphatidic acid (LPA) is a polar lipid metabolite which is involved in a wide range of biological processes, including cell proliferation and migration, wound healing, and increase of endothelial permeability. The present study reports evidences showing that LPA is able to enhance the antimicrobial activity of human macrophages and of bronchoalveolar lavage cells from tuberculosis patients leading to intracellular growth control of Mycobacterium tuberculosis. Such antimicrobial activity is mediated by the activation of phospholipase D which in turn induces acidification of M. tuberculosis containing phagosomes and is associated with the enhanced expression of Cathepsin D. These results suggest the possible protective role of this lysophospholipid in the activation of innate antimycobacterial response. [Copyright &y& Elsevier]