Inhibition of TNF-alpha improves indomethacin-induced enteropathy in rats by modulating iNOS expression.
TNF-alpha, including other proinflammatory cytokines alone or in combination, induces iNOS expression and upregulates inflammatory responses. We evaluated the relationship between TNF-alpha and iNOS expression in indomethacin-induced jejunoileitis in male Sprague-Dawley rats. Rats were fed a daily dose of a phosphodiesterase inhibitor-either theophylline or pentoxifylline-for 2 days. Jejunoileitis was induced with two subcutaneous injections of indomethacin (7.5 mg/kg) 24 hr apart and theophylline or pentoxifylline continued for 12 hr or 4 days. Other rats received a single intraperitoneal injection of anti-TNF-alpha monoclonal antibody (TNF-Ab) 30-min before indomethacin. At 4 days TNF-Ab, theophylline, or pentoxifylline treatment significantly decreased indomethacin-induced ulceration, myeloperoxidase activity, and disease activity index. Although indomethacin significantly increased serum TNF-alpha and nitrate/nitrite levels over the control value as early as 12 hr, iNOS expression was detected only after 4 days. Serum IL-1beta level did not change at 12 hr but increased fourfold at 4 days. Treatment with TNF-Ab, theophylline, or pentoxifylline significantly reduced serum/tissue TNF-alpha, IL-1beta, nitrate/nitrite, and iNOS expression. The downregulation of nitrate/nitrite by these inhibitors suggests that TNF-alpha modulates iNOS expression.
Saud
B
B
Department of Medicine, Division of Gastroenterology, SUNY Upstate Medical University, Syracuse, New York, 13210, USA.
Nandi
J
J
Ong
G
G
Finocchiaro
S
S
Levine
R A
RA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000633:toxicity*; D000911:Antibodies, Monoclonal; D015536:Down-Regulation; D007079:Ileitis / Q000139:chemically induced* / Q000276:immunology / Q000662:veterinary; D007213:Indomethacin / Q000494:pharmacology* / Q000633:toxicity*; D007249:Inflammation; D007579:Jejunal Diseases / Q000139:chemically induced* / Q000276:immunology / Q000662:veterinary; D008297:Male; D009566:Nitrates; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites; D010431:Pentoxifylline / Q000008:administration & dosage / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013806:Theophylline / Q000008:administration & dosage / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D009566:Nitrates; D009573:Nitrites; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D013806:Theophylline; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D010431:Pentoxifylline; D007213:Indomethacin