Anthrax lethal toxin enhances IkappaB kinase activation and differentially regulates pro-inflammatory genes in human endothelium

Anthrax lethal toxin (LT) was previously shown to enhance transcriptional activity of NF-kappaB in tumor necrosis factor-alpha-activated primary human endothelial cells. Here we show that this LT-mediated increase in NF-kappaB activation is associated with the enhanced degradation of the inhibitory...

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Bibliographic Details
Published in:The Journal of biological chemistry 2009-09, Vol.284 (38), p.25761
Main Authors: Warfel, Jason M, D'Agnillo, Felice
Format: Article
Language:English
Subjects:
Anthrax - enzymology
Antigens, Bacterial - metabolism
Antigens, Bacterial - pharmacology
Bacterial Toxins - metabolism
Bacterial Toxins - pharmacology
CD40 Antigens - biosynthesis
Cells, Cultured
Chemokine CCL2 - biosynthesis
Endothelial Cells - enzymology
Endothelium, Vascular - enzymology
Enzyme Activation - drug effects
Gene Expression Regulation - drug effects
Humans
I-kappa B Kinase - metabolism
I-kappa B Proteins - metabolism
Inflammation - enzymology
Transcription Factor AP-1 - metabolism
Transcription Factor RelA - metabolism
Transcription, Genetic - drug effects
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Summary:Anthrax lethal toxin (LT) was previously shown to enhance transcriptional activity of NF-kappaB in tumor necrosis factor-alpha-activated primary human endothelial cells. Here we show that this LT-mediated increase in NF-kappaB activation is associated with the enhanced degradation of the inhibitory proteins IkappaBalpha and IkappaBbeta but not IkappaBepsilon. Moreover, this was accompanied by enhanced activation of the IkappaB kinase complex (IKK), which is responsible for targeting IkappaB proteins for degradation. Importantly, LT enhancement of IkappaBalpha degradation was completely blocked by a selective IKKbeta inhibitor, whereas IkappaBbeta degradation was attenuated, suggesting a mechanistic link. Consistent with the above data, LT-cotreated cells show elevated phosphorylation of two IKK substrates, IkappaBalpha and p65, both of which were blocked by incubation with the IKKbeta inhibitor. Consistent with NF-kappaB activation, LT increased transcription of the NF-kappaB regulated gene CD40. Conversely, LT inhibited transcription of another NF-kappaB-regulated gene, CCL2. This inhibition was linked to the LT-mediated suppression of another CCL2-regulating transcription factor, AP-1 (activator protein-1). These data suggest that LT-mediated enhancement of NF-kappaB is IKK-dependent, but importantly, the net effect of LT on the transcription of proinflammatory genes is driven by the cumulative effect of LT on the particular set of transcription factors that regulate a given promoter. Together, these findings provide new mechanistic insight on how LT may disrupt the host response to anthrax.
ISSN:1083-351X
DOI:10.1074/jbc.M109.036970