Different sensitivity of lamina propria T-cell subsets to nitric oxide-induced apoptosis explains immunomodulatory activity of a nitric oxide-releasing derivative of mesalamine in rodent colitis.
OBJECTIVE
Uncontrolled T-cell activation plays a critical role in the pathogenesis of inflammatory bowel diseases. Therefore, pharmacological strategies directed toward restoring the normal responsiveness of the immune system could be effective in the treatment of these pathologic conditions. The addition of a nitric oxide-releasing moiety to conventional drugs, such as aspirin and other anti-inflammatory analgesic drugs, results in new chemical entities with potent immunomodulatory activities. The aim of this study was to investigate the immunomodulatory activity of a nitric oxide-releasing derivative of mesalamine (NCX-456), as compared with standard mesalamine, in 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice.


METHODS
Cells and tissues from mice with 2,4,6-trinitrobenzene sulfonic acid-induced colitis and from interleukin 10-deficient mice with spontaneous chronic colitis receiving treatment with several doses of NCX-456 or mesalamine were analyzed for morphology, cytokine production, and apoptosis.


RESULTS
NCX-456, but not mesalamine, administration resulted in a marked reduction in clinical, histological, and immunologic signs of colitis in both models. NCX-456 inhibited the release of T-helper type 1-derived cytokines and increased the release of the regulatory T cell-derived cytokines interleukin 10 and transforming growth factor beta. In vitro analyses showed that NCX-456 inhibited proliferation and caused selective apoptosis of the subset of activated lamina propria T-helper type 1 cells, whereas it was ineffective for regulatory T-cell function and survival.


CONCLUSIONS
Collectively, these data show that NCX-456 inhibits lamina propria T-helper type 1 function and stimulates the activity of interleukin 10- and transforming growth factor beta-secreting cells, thus restoring mucosal immune homeostasis and suppressing intestinal inflammation.
Santucci
Luca
L
Clinica di Gastroenterologia ed Epatologia, Dipartimento di Medicina Clinica e Sperimentale, Università di Perugia, Italy. lsant@unipg.it
Wallace
John
J
Mencarelli
Andrea
A
Farneti
Silvana
S
Morelli
Antonio
A
Fiorucci
Stefano
S
D000636:Aminosalicylic Acids / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D003106:Colon / Q000166:cytology / Q000276:immunology; D007155:Immunologic Factors / Q000494:pharmacology; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007155:Immunologic Factors; C434799:NO-mesalamine; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid