TNF-α modulates iNOS expression in an experimental rat model of indomethacin-induced jejunoileitis

• Published in: Molecular and cellular biochemistry Vol. 336; no. 1-2; pp. 17 - 24
• Main Authors: Nandi, Jyotirmoy, Saud, Bipin, Zinkievich, J. Michael, Yang, Zhong-jin, Levine, Robert A.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-03-2010
• Subjects: Animals; Biochemistry; Biomedical and Life Sciences; Cardiology; Dose-Response Relationship, Drug; Enteritis - blood; Enteritis - chemically induced; Enteritis - metabolism; Hyperbaric Oxygenation; Ileitis - blood; Ileitis - chemically induced; Ileitis - metabolism; Ileum - enzymology; Ileum - metabolism; Indomethacin - toxicity; Interleukin-1beta - blood; Interleukin-1beta - metabolism; Intestinal Mucosa - enzymology; Intestinal Mucosa - metabolism; Jejunal Diseases - blood; Jejunal Diseases - chemically induced; Jejunal Diseases - metabolism; Jejunum - enzymology; Jejunum - metabolism; Life Sciences; Male; Medical Biochemistry; Nitrates - blood; Nitric Oxide Synthase Type II - metabolism; Nitrites - blood; Oncology; Peroxidase - metabolism; Phosphodiesterase Inhibitors - pharmacology; Random Allocation; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Specific Pathogen-Free Organisms; Time Factors; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - blood; Tumor Necrosis Factor-alpha - physiology; Phosphodiesterase inhibitor; Hyperbaric oxygenation; Intestinal ulceration; IL-1β; Nitric oxide; Anti-TNF-α antibody
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-009-0259-2

Multiple mucosal immune factors, such as TNF-α and IL-1β, are thought to be key mediators involved in inflammatory bowel disease. We evaluated the role of the pro-inflammatory cytokine TNF-α on nitric oxide synthase (NOS) expression in indomethacin-induced jejunoileitis in rats. Jejunoileitis was induced in rats with subcutaneous injections of indomethacin (7.5 mg/kg) 24 h apart for two consecutive days, and animals were randomized into four groups. Group 1 received only indomethacin. Group 2 was treated with a daily dose of phosphodiesterase (PDE) inhibitor (theophylline or pentoxifylline) by oral gavage for 2 days before and 4 days after indomethacin. Group 3 received a single dose of anti-TNF-α monoclonal antibody (TNF-Ab, IP) 30 min before indomethacin. Group 4 was treated with 1 h hyperbaric oxygenation (HBO
2
) for 5 days after indomethacin. Rats were sacrificed at 12 h or 4 days after final indomethacin injection. PDE inhibitor, TNF-Ab, or HBO
2
treatment significantly decreased indomethacin-induced ulceration, myeloperoxidase activity, and disease activity index. Although indomethacin significantly increased serum TNF-α and nitrate/nitrite (NO
x
) concentrations above control values at 12 h, inducible NOS (iNOS) expression was detected only at day 4. Serum IL-1β levels did not change at 12 h but increased 4-fold after 4 days. Indomethacin had no effect on constitutive NOS. Treatment with PDE inhibitor, TNF-Ab, or HBO
2
significantly reduced serum/tissue TNF-α, IL-1β, NO
x
, and iNOS expression. Our data show TNF-α plays an early pro-inflammatory role in indomethacin-induced jejunoileitis. Additionally, down-regulation of NO
x
by PDE inhibitors, TNF-Ab, or HBO
2
suggests that TNF-α modulates iNOS expression.