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.

Abstract

BACKGROUND & AIMS:

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.

• Authors: Luca Santucci, John Wallace, Andrea Mencarelli, Silvana Farneti, Antonio Morelli, Stefano Fiorucci
• Journal: Gastroenterology (Gastroenterology) Vol. 128 Issue 5 Pg. 1243-57 (May 2005) ISSN: 0016-5085 [Print] United States
• PMID: 15887108 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminosalicylic Acids
• Anti-Inflammatory Agents, Non-Steroidal
• Immunologic Factors
• NO-mesalamine
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• Interleukin-10
• Nitric Oxide
• Interferon-gamma
• Trinitrobenzenesulfonic Acid

Topics

• Aminosalicylic Acids (pharmacology)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Apoptosis (drug effects, immunology)
• Cells, Cultured
• Colitis (chemically induced, drug therapy, immunology)
• Colon (cytology, immunology)
• Immunologic Factors (pharmacology)
• In Vitro Techniques
• Interferon-gamma (metabolism)
• Interleukin-10 (genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Mutant Strains
• Mitochondria (drug effects, metabolism)
• Nitric Oxide (metabolism)
• Reactive Oxygen Species (metabolism)
• T-Lymphocyte Subsets (cytology, drug effects, immunology)
• Th1 Cells (cytology, drug effects, immunology)
• Trinitrobenzenesulfonic Acid
• Tumor Necrosis Factor-alpha (metabolism)