NCX-1015, a nitric-oxide derivative of prednisolone, enhances regulatory T cells in the lamina propria and protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice.
NCX-1015 is a nitric oxide (NO)-releasing derivative of prednisolone. In this study we show NCX-1015 protects mice against the S. A. development and induces healing of T helper cell type 1-mediated experimental colitis induced by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). The beneficial effect of NCX-1015 was reflected in increased survival rates, improvement of macroscopic and histologic scores, a decrease in the mucosal content of T helper cell type 1 cytokines (protein and mRNA), and diminished myeloperoxidase activity in the colon. In contrast to its NO derivative, only very high doses of prednisolone were effective in reproducing these beneficial effects. NCX-1015 was 10- to 20-fold more potent than the parent compound in inhibiting IFN-gamma secretion by lamina propria mononuclear cells. Protection against developing colitis correlated with inhibition of nuclear translocation of p65Rel A in these cells. In vivo treatment with NCX-1015 potently stimulated IL-10 production, suggesting that the NO steroid induces a regulatory subset of T cells that negatively modulates intestinal inflammation.
Fiorucci
Stefano
S
Clinica di Gastroenterologia ed Endoscopia Digestiva, Dipartimento di Medicina Clinica, Patologia Università di Perugia, Italy. fiorucci@unipg.it
Antonelli
Elisabetta
E
Distrutti
Eleonora
E
Del Soldato
Piero
P
Flower
Roderick J
RJ
Clark
Mark J Paul
MJ
Morelli
Antonio
A
Perretti
Mauro
M
Ignarro
Louis J
LJ
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology; D008222:Lymphokines / Q000096:biosynthesis; D008297:Male; D008643:Mesentery / Q000098:blood supply; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology; D009195:Peroxidase / Q000032:analysis; D011239:Prednisolone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D051996:Transcription Factor RelA; D014302:Trinitrobenzenesulfonic Acid / Q000037:antagonists & inhibitors* / Q000633:toxicity
D000893:Anti-Inflammatory Agents; D008222:Lymphokines; D016328:NF-kappa B; D051996:Transcription Factor RelA; C418962:prednisolone 21-((4'-nitrooxymethyl)benzoate); D016753:Interleukin-10; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid; D011239:Prednisolone; D009195:Peroxidase