Bacillus anthracis lethal toxin (LT) impairs innate and adaptive immunity. Anthrax lethal factor stimulates cleavage of MAPK kinases, which prevents the activation of antiapoptotic MAPK targets. However, these MAPK targets have not been yet identified. Here, we found that LT induces macrophage apoptosis by enhancing caspase 8 activation and by preventing the activation of ribosomal S6 kinase-2 (RSK), a MAPK target, and the phosphorylation of CCAAT/enhancer binding protein-beta (C/EBPbeta) on T(217), a RSK target. Expression of the dominant positive, phosphorylation mimic C/EBPbeta-E(217) rescued macrophages from LT-induced apoptosis by blocking the activation of procaspase 8. LT inhibited macrophage phagocytosis and oxidative burst and induced apoptosis in normal mice but not in C/EBPbeta-E(217) transgenic mice. These findings suggest that C/EBPbeta may play a critical role in anthrax pathogenesis, at least in macrophages.
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