Scientific Publications by FDA Staff

J Immunol 2008 Jun 1;180(11):7516-24

Anthrax Lethal Toxin Enhances TNF-Induced Endothelial VCAM-1 Expression via an IFN Regulatory Factor-1-Dependent Mechanism.

Warfel JM, D'Agnillo F

D'Agnillo, F, US FDA, Ctr Biol Evaluat & Res, Lab Biochem & Vasc Biol, Div Hematol, 29 Lincoln Dr,Bldg 29,Room 129, Bethesda, MD 20892 USA US FDA, Ctr Biol Evaluat & Res, Lab Biochem & Vasc Biol, Div Hematol, Bethesda, MD 20892 USA Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, Washington, DC 20057 USA

Impaired host defenses and vascular dysfunction are hallmarks of the late, antibiotic-refractory stages of systemic anthrax infection. Anthrax lethal toxin (LT), a key virulence factor of Bacillus anthracis, was previously shown to enhance VCAM-1 expression on primary human endothelial cells suggesting a causative link between dysregulated adhesion molecule expression and the poor immune response and vasculitis associated with anthrax. In this study, we report that LT amplification of TNF-induced VCAM-1 expression is driven transcriptionally by the cooperative activation of NF-kappaB and IFN regulatory factor-1 (IRF-1). LT enhancement of NF-kappaB phosphorylation and nuclear translocation correlated temporally with a delayed reaccumulation of IkappaBalpha, while increased induction of IRF-1 was linked to STAT1 activation. LT failed to augment TNF-induced ICAM-1 or E-selectin expression, two adhesion molecules regulated by NF-kappaB, but not IRF-1. These results suggest that LT can differentially modulate NF-kappaB target genes and highlight the importance of IRF-1 in VCAM-1 enhancement. Altering the activity of key transcription factors involved in host response to infection may be a critical mechanism by which LT contributes to anthrax pathogenesis.