B-225. The Activation of NF-κB Pathway Is Associated with Anthrax Lethal Toxin Induced Apoptosis of Bovine Macrophage

X. Liang1, C. Gao2, M. Rutherford1, Y. Ji1;
1Univ. of Minnesota, St. Paul, MN, 2Van Andel Res. Inst., Grand Rapids, MI.

Anthrax lethal toxin (LeTx) is a key virulence factor to cause lethal effect on both animal and human infected with Bacillus anthracis. It has been demonstrated that macrophages are likely to be the primary target of LeTx, and that herbivores are susceptible and carnivores are insensitive to B. anthracis. However, the cellular mechanism of LeTx-induced death of herbivores is still unclear. In this study, we examined signal pathways involved in LeTx-induced cell death using bovine macrophage. Our results showed that LeTx effectively induced apoptosis of the macrophage and that the inhibition of caspase activation with specific inhibitors eliminated LeTx-induced cell death. Specifically, we found that in the LeTx-sensitive bovine macrophage LeTx efficiently triggered the degradation of I-κB and increased the NF-κB nuclear translocation, whereas had no effect in the LeTx-insensitive dog-derived macrophage. Inhibiting NF-κB activation with either chemical inhibitors or a negative dominant super-repressor I-κBαm totally blocked LeTx-induced cell death. Moreover, lethal toxin significantly up-regulated the expression of TNF-α in an activated NF-κB dependent manner; inhibition of the release of TNF-α with a specific inhibitor decreased lethal toxin-induced cell death. The above data suggest that the activation of NF-κB pathway is important for LeTx to cause apoptosis of the sensitive macrophage. The identification of NF-κB as a key signal pathway for cytotoxicity of anthrax lethal toxin may provide new insight into pathogenesis of anthrax.