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

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.

Tobacco exposure and susceptibility to tuberculosis: Is there a smoking gun?

“…Furthermore, AM incubated with AIM showed a significant increase in Bcl-xL expression, a pro-survival, anti-apoptotic molecule. We have found that NFkB e well known to be activated by both CS and exogenous ROS e is a potent inhibitor of apoptosis and autophagy in human macrophages, ultimately impairing control of MTB [13]. This finding is corroborated by studies showing that nicotine inhibits apoptosis [28].…”

“…AM can be classified into two main subtypes: (i) the classically-activated M1 phenotype, characterized by production of pro-inflammatory cytokines and IFNg-inducible gene expression and (ii) the alternatively-activated M2 or "deactivated" phenotype, characterized by increased activity of arginase, matrix metalloproteinase (MMP), transforming growth factor-beta (TGFb), IL-10, and prostaglandin E 2 [11,12]. M1 macrophages orchestrate host protective responses against MTB by producing cytokines, chemokines, and adhesion molecules that recruit and activate other immune cells but also directly kill MTB by phagosome-lysosome (P-L) fusion, autophagy, and apoptosis or at least help contain the infection by participating in the formation of well-formed granulomas [13,14]. M1 macrophages also process mycobacterial antigens and activate IFNg-producing CD4 þ and CD8 þ T cells that are vital for controlling MTB infection.…”

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

“…We found that granulomas in the containment set have shorter NF-B signal activation intervals than those granulomas in the disseminating set. Recently, Bai et al published work suggesting that inhibition of NF-B activation (i.e., shorter signal activation intervals) decreases survival of M. tuberculosis in human macrophages (112). They used an inhibitor of IBa kinase to inhibit NF-B activation and found a significant decrease in the number of viable intracellular mycobacteria recovered from THP-1 macrophages at both 4 and 8 days after infection.…”

A Mycobacterial Phosphoribosyltransferase Promotes Bacillary Survival by Inhibiting Oxidative Stress and Autophagy Pathways in Macrophages and Zebrafish

“…NF-B inhibition induces autophagy by increasing the formation of autophagosomes (106), and MAPK triggers the expression of NF-B (107,108). This suggests that MsmRv3242c infection activates the MAPK pathway, which subsequently activates p-NF-B and IL-10, resulting in inhibition of autophagy.…”