Division of Gastroenterology, Department of Medicine, State University of New York, Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
Mol Cell Biochem. 2010 Mar;336(1-2):17-24. doi: 10.1007/s11010-009-0259-2. Epub 2009 Oct 3.
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.
多种黏膜免疫因子，如 TNF-α 和 IL-1β，被认为是参与炎症性肠病的关键介质。我们评估了促炎细胞因子 TNF-α 在吲哚美辛诱导的大鼠空回肠炎中的一氧化氮合酶（NOS）表达中的作用。大鼠皮下注射吲哚美辛（7.5mg/kg），24 小时后连续两天，将动物随机分为四组。第 1 组仅接受吲哚美辛。第 2 组在吲哚美辛前 2 天和后 4 天每天通过口服给予磷酸二酯酶（PDE）抑制剂（茶碱或己酮可可碱）。第 3 组在吲哚美辛前 30 分钟给予 TNF-α 单克隆抗体（TNF-Ab，IP）单次剂量。第 4 组在吲哚美辛后 5 天接受 1 小时高压氧（HBO(2))治疗。最后一次吲哚美辛注射后 12 小时或 4 天处死大鼠。PDE 抑制剂、TNF-Ab 或 HBO(2)治疗显著降低了吲哚美辛诱导的溃疡、髓过氧化物酶活性和疾病活动指数。虽然吲哚美辛在 12 小时显着增加了血清 TNF-α 和硝酸盐/亚硝酸盐（NOx）浓度，但仅在第 4 天检测到诱导型 NOS（iNOS）表达。血清 IL-1β 水平在 12 小时内没有变化，但在第 4 天增加了 4 倍。吲哚美辛对组成型 NOS 没有影响。PDE 抑制剂、TNF-Ab 或 HBO(2)治疗显着降低了血清/组织 TNF-α、IL-1β、NOx 和 iNOS 表达。我们的数据表明 TNF-α 在吲哚美辛诱导的空回肠炎中发挥早期促炎作用。此外，PDE 抑制剂、TNF-Ab 或 HBO(2)下调 NOx 表明 TNF-α 调节 iNOS 表达。
