Endogenous corticosteroids modulate Clostridium difficile toxin A-induced enteritis in rats.
We examined the role of glucocorticoids in acute inflammatory diarrhea mediated by Clostridium difficile toxin A. Toxin A (5 microg) or buffer was injected in rat ileal loops, and intestinal responses were measured after 30 min to 4 h. Ileal toxin A administration increased plasma glucocorticoids after 1 h, at which time the toxin-stimulated secretion was not significant. Administration of the glucocorticoid analog dexamethasone inhibited toxin A-induced intestinal secretion and inflammation and downregulated toxin A-mediated increase of macrophage inflammatory protein-2. Adrenalectomy followed by replacement with glucocorticoids at various doses suggested that intestinal responses to toxin A were related to circulating levels of glucocorticoids. Administration of the glucocorticoid receptor antagonist RU-486 enhanced toxin A-mediated intestinal secretion and inflammation. We conclude that C. difficile toxin A causes increased secretion of endogenous glucocorticoids, which diminish the intestinal secretory and inflammatory effects of toxin A.
Castagliuolo
I
I
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Massachusetts, Boston 02215, USA.
Karalis
K
K
Valenick
L
L
Pasha
A
A
Nikulasson
S
S
Wlk
M
M
Pothoulakis
C
C
D000315:Adrenalectomy; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D054426:Chemokine CXCL2; D002630:Chemotactic Factors / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D004751:Enteritis / Q000139:chemically induced / Q000517:prevention & control*; D004768:Enterotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D005938:Glucocorticoids / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D015846:Monokines / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D001427:Bacterial Toxins; D054426:Chemokine CXCL2; D002630:Chemotactic Factors; D004768:Enterotoxins; D005938:Glucocorticoids; D006727:Hormone Antagonists; D015846:Monokines; C041348:tcdA protein, Clostridium difficile; D015735:Mifepristone; D003907:Dexamethasone