Abstract |
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.
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Authors | Stefano Fiorucci, Elisabetta Antonelli, Eleonora Distrutti, Piero Del Soldato, Roderick J Flower, Mark J Paul Clark, Antonio Morelli, Mauro Perretti, Louis J Ignarro |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 99
Issue 24
Pg. 15770-5
(Nov 26 2002)
ISSN: 0027-8424 [Print] United States |
PMID | 12427966
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anti-Inflammatory Agents
- Lymphokines
- NF-kappa B
- Transcription Factor RelA
- prednisolone 21-((4'-nitrooxymethyl)benzoate)
- Interleukin-10
- Interferon-gamma
- Trinitrobenzenesulfonic Acid
- Prednisolone
- Peroxidase
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Topics |
- Active Transport, Cell Nucleus
(drug effects)
- Animals
- Anti-Inflammatory Agents
(pharmacology)
- Colitis
(chemically induced, drug therapy, pathology, prevention & control)
- Drug Evaluation, Preclinical
- Endothelium, Vascular
(drug effects, pathology)
- Interferon-gamma
(biosynthesis)
- Interleukin-10
(biosynthesis)
- Intestinal Mucosa
(drug effects, pathology)
- Lymphokines
(biosynthesis)
- Male
- Mesentery
(blood supply)
- Mice
- Mice, Inbred BALB C
- Models, Animal
- NF-kappa B
(metabolism)
- Neutrophils
(enzymology)
- Peroxidase
(analysis)
- Prednisolone
(analogs & derivatives, pharmacology)
- T-Lymphocyte Subsets
(drug effects, immunology)
- Transcription Factor RelA
- Trinitrobenzenesulfonic Acid
(antagonists & inhibitors, toxicity)
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