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.

• Authors: Xiyuan Bai, Nicole E Feldman, Kathryn Chmura, Alida R Ovrutsky, Wen-Lin Su, Laura Griffin, Dohun Pyeon, Mischa T McGibney, Matthew J Strand, Mari Numata, Seiji Murakami, Loretta Gaido, Jennifer R Honda, William H Kinney, Rebecca E Oberley-Deegan, Dennis R Voelker, Diane J Ordway, Edward D Chan
• Journal: PloS one (PLoS One) Vol. 8 Issue 4 Pg. e61925 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23634218 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 3-(4-methylphenylsulfonyl)-2-propenenitrile
• Caspase Inhibitors
• NF-kappa B
• Nitriles
• Sulfones
• Caspase 3

Topics

• Adenoviridae (genetics)
• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Caspase 3 (metabolism)
• Caspase Inhibitors (pharmacology)
• Cell Line
• Humans
• Intracellular Space (drug effects, metabolism, microbiology)
• Macrophages (cytology, immunology, metabolism, microbiology)
• Microbial Viability (drug effects)
• Mycobacterium tuberculosis (drug effects, physiology)
• NF-kappa B (antagonists & inhibitors, genetics, metabolism)
• Nitriles (pharmacology)
• Sulfones (pharmacology)