title: Anthrax lethal toxin enhances TNF-induced endothelial VCAM-1 expression via an IFN regulatory factor-1-dependent mechanism.
abstract: 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.
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Warfel
authors.forename: Felice
authors.initials: F
authors.lastname: D'Agnillo
mesh_terms: D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism*; D001427:Bacterial Toxins / Q000276:immunology / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D019040:E-Selectin / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D050989:GATA2 Transcription Factor / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D019040:E-Selectin; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D016328:NF-kappa B; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C030325:anthrax toxin; D018799:Intercellular Adhesion Molecule-1; D011494:Protein Kinases; C065999:Sp1 kinase