Abstract
Nuclear factor-kappa B (NFκB) is a ubiquitous transcription factor that mediates pro-inflammatory responses required for host control of many microbial pathogens; on the other hand, NFκB has been implicated in the pathogenesis of other inflammatory and infectious diseases. Mice with genetic disruption of the p50 subunit of NFκB are more likely to succumb to Mycobacterium tuberculosis (MTB). However, the role of NFκB in host defense in humans is not fully understood. We sought to examine the role of NFκB activation in the immune response of human macrophages to MTB. Targeted pharmacologic inhibition of NFκB activation using BAY 11-7082 (BAY, an inhibitor of IκBα kinase) or an adenovirus construct with a dominant-negative IκBα significantly decreased the number of viable intracellular mycobacteria recovered from THP-1 macrophages four and eight days after infection. The results with BAY were confirmed in primary human monocyte-derived macrophages and alveolar macrophages. NFκB inhibition was associated with increased macrophage apoptosis and autophagy, which are well-established killing mechanisms of intracellular MTB. Inhibition of the executioner protease caspase-3 or of the autophagic pathway significantly abrogated the effects of BAY. We conclude that NFκB inhibition decreases viability of intracellular MTB in human macrophages via induction of apoptosis and autophagy.
Highlights
Tuberculosis (TB) remains problematic throughout much of the world due, in large part, to burgeoning drug resistance and human immunodeficiency virus (HIV) co-infection [1,2,3]
Inhibition of Nuclear factor-kappa B (NFkB) activation reduced the viability of intracellular Mycobacterium tuberculosis (MTB) through increased induction of apoptosis and autophagy
While we showed that inhibition of NFkB enhanced macrophage response to MTB, it is important to note that NFkB is a ubiquitous transcription factor involved in many cellular processes associated with inflammation and infections
Summary
Tuberculosis (TB) remains problematic throughout much of the world due, in large part, to burgeoning drug resistance and human immunodeficiency virus (HIV) co-infection [1,2,3]. In addition to these critical barriers to TB control, Mycobacterium tuberculosis (MTB) has been highly successful in evading host immune mechanisms and surviving within phagocytes [4,5,6,7]. By inducing an inflammatory response, NFkB activation has been shown to enhance immunity against certain microbial pathogens [22,23]. Specific NFkB-mediated pathways may be exploited by bacterial pathogens to promote survival; e.g., Escherichia coli and Chlamydophila pneumoniae activate NFkB to prevent apoptosis of host cells [22], while Shigella flexneri and Helicobacter pylori induce host NFkB to enhance tissue invasion [24,25]
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