IL-11 inhibits Clostridium difficile toxin A enterotoxicity in rat ileum.
Interleukin-11 (IL-11) is a stromal cell-derived cytokine with several biological activities against hematopoietic cells. Recent results indicated that IL-11 reduced mucosal damage in animal models of colitis. This study aimed to explore the action of recombinant human IL-11 (rhIL-11) on the intestinal effects of Clostridium difficile toxin A, an inflammatory enterotoxin, and cholera toxin, a noninflammatory enterotoxin in rat ileum. We administered rhIL-11 subcutaneously to rats before injection of toxin A into ileal loops and measured fluid secretion, epithelial permeability to mannitol, histopathological damage, and release of rat mast cell protease II (RMCP II) from intestinal mast cells and of tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-2 (MIP-2) from lamina propria macrophages. rhIL-11 (50-1,000 micrograms/kg) inhibited toxin A but not cholera toxin-mediated secretion and permeability in a dose-dependent fashion and reduced toxin A-induced epithelial cell damage. Rats treated with rhIL-11 also showed reduced RMCP II, TNF-alpha, and MIP-2 release in response to toxin A. Exposure of rat peripheral monocytes in vitro to rhIL-11 (1 microgram/ml) inhibited lipopolysaccharide and toxin A-mediated increases in TNF-alpha mRNA and protein levels. We conclude that rhIL-11 blocks the intestinal effects of C. difficile toxin A, possibly by inhibiting release of inflammatory mediators from mucosal mast cells and intestinal macrophages.
Castagliuolo
I
I
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston 02215, USA.
Kelly
C P
CP
Qiu
B S
BS
Nikulasson
S T
ST
LaMont
J T
JT
Pothoulakis
C
C
D000818:Animals; D001427:Bacterial Toxins; D054426:Chemokine CXCL2; D053818:Chymases; D004768:Enterotoxins / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D006801:Humans; D007082:Ileum / Q000187:drug effects* / Q000473:pathology; D017370:Interleukin-11 / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000378:metabolism; D015846:Monokines / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D012697:Serine Endopeptidases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D001427:Bacterial Toxins; D054426:Chemokine CXCL2; D004768:Enterotoxins; D017370:Interleukin-11; D015846:Monokines; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C041348:tcdA protein, Clostridium difficile; D012697:Serine Endopeptidases; D053818:Chymases