The large clostridial toxins from Clostridium sordellii and C. difficile repress glucocorticoid receptor activity.
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).
Tait
A Sasha
AS
Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health/NIH, 5625 Fishers Lane (MSC-9401), Rockville, MD 20852, USA.
Dalton
Monique
M
Geny
Blandine
B
D'Agnillo
Felice
F
Popoff
Michel R
MR
Sternberg
Esther M
EM
D000818:Animals; D019677:Artificial Gene Fusion; D001426:Bacterial Proteins / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D016360:Clostridioides difficile / Q000502:physiology*; D047989:Paraclostridium sordellii / Q000502:physiology*; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004768:Enterotoxins / Q000494:pharmacology*; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D010766:Phosphorylation; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; C072292:lethal toxin LT, Clostridium sordellii; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile; D003907:Dexamethasone; D008156:Luciferases; D048051:p38 Mitogen-Activated Protein Kinases