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Anthrax Lethal Toxin Enhances TNF-Induced Endothelial VCAM-1 Expression via an IFN Regulatory Factor-1-Dependent Mechanism¹

Jason M. Warfel^*, and Felice D'Agnillo^2,*

^* Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892; and Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057

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-B and IFN regulatory factor-1 (IRF-1). LT enhancement of NF-B phosphorylation and nuclear translocation correlated temporally with a delayed reaccumulation of IB, 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-B, but not IRF-1. These results suggest that LT can differentially modulate NF-B 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Office of Women’s Health, Food and Drug Administration. This project was supported in part by an appointment of J.M.W. to the National Institutes of Health–Georgetown University Graduate Partnership Program and the Research Fellowship Program for the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.

² Address correspondence and reprint requests to Dr. Felice D’Agnillo, Center for Biologics Evaluation and Research, Food and Drug Administration, 29 Lincoln Drive, Building 29, Room 129, Bethesda, MD 20892. E-mail address: felice.dagnillo{at}fda.hhs.gov

³ Abbreviations used in this paper: PA, protective Ag; LF, lethal factor; EF, edema factor; LT, lethal toxin; IRF, IFN regulatory factor; C_T, cycle threshold; ARE, AU-rich element; iNOS, inducible NO synthase.

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The JI 2008 180: 7053-7054. [Full Text]  

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				J. M. Warfel and F. D'Agnillo Anthrax Lethal Toxin Enhances I{kappa}B Kinase Activation and Differentially Regulates Pro-inflammatory Genes in Human Endothelium J. Biol. Chem., September 18, 2009; 284(38): 25761 - 25771. [Abstract] [Full Text] [PDF]