TNF-alpha modulates iNOS expression in an experimental rat model of indomethacin-induced jejunoileitis.
Multiple mucosal immune factors, such as TNF-alpha and IL-1beta, are thought to be key mediators involved in inflammatory bowel disease. We evaluated the role of the pro-inflammatory cytokine TNF-alpha 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-alpha 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-alpha and nitrate/nitrite (NOx) concentrations above control values at 12 h, inducible NOS (iNOS) expression was detected only at day 4. Serum IL-1beta 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-alpha, IL-1beta, NOx, and iNOS expression. Our data show TNF-alpha plays an early pro-inflammatory role in indomethacin-induced jejunoileitis. Additionally, down-regulation of NOx by PDE inhibitors, TNF-Ab, or HBO(2) suggests that TNF-alpha modulates iNOS expression.
Division of Gastroenterology, Department of Medicine, State University of New York, Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA. nandij@upstate.edu
Jyotirmoy
J
Nandi
Bipin
B
Saud
J Michael
JM
Zinkievich
Zhong-Jin
ZJ
Yang
Robert A
RA
Levine
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004751:Enteritis / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D006931:Hyperbaric Oxygenation; D007079:Ileitis / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D007082:Ileum / Q000201:enzymology / Q000378:metabolism; D007213:Indomethacin / Q000633:toxicity*; D053583:Interleukin-1beta / Q000097:blood / Q000378:metabolism; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism; D007579:Jejunal Diseases / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D007583:Jejunum / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009566:Nitrates / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D009573:Nitrites / Q000097:blood; D009195:Peroxidase / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*
D053583:Interleukin-1beta; D009566:Nitrates; D009573:Nitrites; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; D007213:Indomethacin