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Infection and Immunity, August 2007, p. 3935-3940, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00291-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Large Clostridial Toxins from Clostridium sordellii and C. difficile Repress Glucocorticoid Receptor Activity{triangledown}

A. Sasha Tait,1 Monique Dalton,1,# Blandine Geny,2 Felice D'Agnillo,3 Michel R. Popoff,2 and Esther M. Sternberg1*

Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, NIH, Rockville, Maryland,1 Unite des Bacteries Anaerobes et Toxines, Institut Pasteur, Paris, France,2 Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, FDA, Bethesda, Maryland3

Received 21 February 2007/ Returned for modification 9 April 2007/ Accepted 10 May 2007

We have previously shown that Bacillus anthracis lethal toxin represses glucocorticoid receptor (GR) transactivation. We now report that repression of GR activity also occurs with the large clostridial toxins produced by Clostridium sordellii and C. difficile. This was demonstrated using a transient transfection assay system for GR transactivation. We also report that C. sordellii lethal toxin inhibited GR function in an ex vivo assay, where toxin reduced the dexamethasone suppression of the proinflammatory cytokine tumor necrosis factor alpha (TNF-{alpha}). Furthermore, the glucocorticoid antagonist RU-486 in combination with C. sordellii lethal toxin additively prevented glucocorticoid suppression of TNF-{alpha}. These findings corroborate the fact that GR is a target for the toxin and suggest a physiological role for toxin-associated GR repression in inflammation. Finally, we show that this repression is associated with toxins that inactivate p38 mitogen-activated protein kinase (MAPK).

* Corresponding author. Mailing address: Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, NIH, 5625 Fishers Lane (MSC-9401), Rockville, MD 20852. Phone: (301) 402-2773. Fax: (301) 496-6095. E-mail: sternbee{at}mail.nih.gov

{triangledown} Published ahead of print on 21 May 2007.

Editor: A. D. O'Brien

# Present address: The Methodist Hospital Research Institute, Genitourinary Oncology, Houston, TX 77030.

Infection and Immunity, August 2007, p. 3935-3940, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00291-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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