C/EBPβ phosphorylation rescues macrophage dysfunction and apoptosis induced by anthrax lethal toxin

C/EBP beta phosphorylation rescues macrophage dysfunction and apoptosis induced by anthrax lethal toxin. Am J Physiol Cell Physiol 293: C1788-C1796, 2007. First published September 13, 2007; doi:10.1152/ajpcell.00141.2007. -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/EBP beta) on T-217, a RSK target. Expression of the dominant positive, phosphorylation mimic C/ EBP beta-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/EBP beta- E-217 transgenic mice. These findings suggest that C/EBP beta may play a critical role in anthrax pathogenesis, at least in macrophages.