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Anthrax lethal toxin down-regulates type-IIA secreted phospholipase A(2) expression through MAPK/NF-kappaB
Benoit Raymond1, Lucas Ravaux, Sylvie Mémet
1Institut Pasteur, Paris, France.
Biochemical Pharmacology
|December 8, 2009
Summary
Bacillus anthracis lethal toxin (LT) inhibits secreted phospholipase A2 (sPLA2-IIA) expression in host cells. This occurs by interfering with MAPK-NF-kappaB signaling, a key pathway for immune defense against anthrax.
Area of Science:
- Immunology
- Microbiology
- Molecular Biology
Background:
- Bacillus anthracis lethal toxin (LT) targets MAPK-kinases.
- Secreted type-IIA phospholipase A2 (sPLA2-IIA) has potent anthracidal activity.
- LT inhibits sPLA2-IIA expression in macrophages.
Purpose of the Study:
- To investigate the mechanisms by which LT inhibits sPLA2-IIA expression.
- To elucidate the roles of MAPK and NF-kappaB signaling pathways in this inhibition.
Main Methods:
- In vitro studies using guinea pig alveolar macrophages and CHO cells.
- Chemical inhibitors and dominant-negative/active constructs for p38 and ERK MAPKs.
- Reporter gene assays for sPLA2-IIA promoter and NF-kappaB activity.
- In vivo studies involving LT administration in guinea pigs followed by LPS challenge.
Main Results:
- p38 and ERK MAPKs are involved in sPLA2-IIA expression.
- LT inhibits IL-1beta-induced p38 phosphorylation and sPLA2-IIA promoter activity.
- LT and dominant-negative p38 decreased NF-kappaB activity, while active p38 enhanced it.
- LT did not affect LPS-induced IkappaBalpha degradation or NF-kappaB nuclear translocation.
- In vivo LT administration reduced sPLA2-IIA levels in broncho-alveolar lavages and ears.
Conclusions:
- sPLA2-IIA expression is regulated by sequential MAPK-NF-kappaB activation.
- LT inhibits sPLA2-IIA expression by interfering with NF-kappaB transactivation.
- This LT-mediated inhibition is a potential mechanism for B. anthracis to subvert host defenses.
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