Inhibition of Nuclear Factor-Kappa B Activation Decreases Survival of Mycobacterium tuberculosis in Human Macrophages. e61925

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 NF Kappa B 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 I Kappa B alpha 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.