Submitted on April 4, 2007
Accepted on September 10, 2007
C/EBP
Phosphorylation Rescues Macrophage Disfunction and Apoptosis Induced by Anthrax Lethal Toxin
Martina Buck1* and Mario Chojkier2
1 Medicine, UCSD, San Diego, California, United States; GI, VAMC, San Diego, Arkansas, United States
2 Medicine, UCSD, San Diego, California, United States; GI, VAMC, San Diego, California, United States
* To whom correspondence should be addressed. E-mail: mbuck{at}vapop.ucsd.edu.
Bacillus anthracis lethal toxin [LT] impairs innate and adaptive immunity. Anthrax lethal factor stimulates cleavage of mitogen-activated protein kinase [MAPK] kinases, which prevents activation of anti-apoptotic 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 the CCAAT/Enhancer Binding Protein [C/EBP]-
on T217, a RSK target. Expression of the dominant positive, phosphorylation mimic C/EBPE217 rescued macrophages from LT-induced apoptosis by blocking the activation of procaspase 8. LT induced apoptosis of spleen macrophages in normal, but not in C/EBPE217 transgenic, mice. These findings suggest that C/EBP may play a critical role in anthrax pathogenesis, at least in macrophages.
