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

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Abstract

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 (HBO2) for 5 days after indomethacin. Rats were sacrificed at 12 h or 4 days after final indomethacin injection. PDE inhibitor, TNF-Ab, or HBO2 treatment significantly decreased indomethacin-induced ulceration, myeloperoxidase activity, and disease activity index. Although indomethacin significantly increased serum TNF-α and nitrate/nitrite (NOx) 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 HBO2 significantly reduced serum/tissue TNF-α, IL-1β, NOx, and iNOS expression. Our data show TNF-α plays an early pro-inflammatory role in indomethacin-induced jejunoileitis. Additionally, down-regulation of NOx by PDE inhibitors, TNF-Ab, or HBO2 suggests that TNF-α modulates iNOS expression.

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Medicine, State University of New York, Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA

    Jyotirmoy Nandi, Bipin Saud, J. Michael Zinkievich & Robert A. Levine

  2. Department of Anesthesiology, State University of New York, Upstate Medical University, Syracuse, New York, USA

    Zhong-jin Yang

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  1. Jyotirmoy Nandi
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  2. Bipin Saud
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Correspondence to Jyotirmoy Nandi.

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Nandi, J., Saud, B., Zinkievich, J.M. et al. TNF-α modulates iNOS expression in an experimental rat model of indomethacin-induced jejunoileitis. Mol Cell Biochem 336, 17–24 (2010). https://doi.org/10.1007/s11010-009-0259-2

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