Inhibition of Nuclear Factor-Kappa B Activation Decreases Survival of Mycobacterium tuberculosis in Human Macrophages

Nuclear factor-kappa B (NF kappa B) is a ubiquitous transcription factor that mediates pro-inflammatory responses required for host control of many microbial pathogens; on the other hand, NF kappa B has been implicated in the pathogenesis of other inflammatory and infectious diseases. Mice with genetic disruption of the p50 subunit of NF kappa B are more likely to succumb to Mycobacterium tuberculosis (MTB). However, the role of NF kappa B in host defense in humans is not fully understood. We sought to examine the role of NFkB activation in the immune response of human macrophages to MTB. Targeted pharmacologic inhibition of NF kappa B activation using BAY 11-7082 (BAY, an inhibitor of I kappa B alpha kinase) or an adenovirus construct with a dominant-negative IkBa 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. NF kappa B 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 NF kappa B inhibition decreases viability of intracellular MTB in human macrophages via induction of apoptosis and autophagy.