Effects of Glutamine on Proinflammatory Gene Expression and Activation of Nuclear Factor Kappa B and Signal Transducers and Activators of Transcription in TNBS-induced Colitis
Effects of Glutamine on Proinflammatory Gene Expression and Activation of Nuclear Factor Kappa B and Signal Transducers and Activators of Transcription in TNBS-induced Colitis
复制标题
DOI：
10.1002/ibd.20543
复制
发表时间：
2008-11-01
影响因子：
4.9
通讯作者：
Tunon, Maria J.
中科院分区：
文献类型：
--
作者：
Kretzmann, Nelson A.;Fillmann, Henrique;Tunon, Maria J.
背景：我们研究了谷氨酰胺对实验性结肠炎大鼠模型中促炎基因表达和核因子κ B （nf - κ B）及转录信号转导和激活因子（STAT）激活的影响。方法：用30mg 2,4,6-三硝基苯磺酸（TNBS）灌胃诱导雄性Wistar大鼠结肠炎。谷氨酰胺（25 mg/kg）每日经直肠给药，连用7天。结果：谷氨酰胺显著降低TNBS动物的总损伤和组织病理学评分，防止肛门压力下降和脊髓过氧化物酶活性升高。TNBS诱导血管细胞黏附分子（VCAM-1）、诱导型一氧化氮合酶（iNOS）和环氧化酶-2 （COX-2）蛋白水平显著升高。这些炎症事件与细胞核中NF-kappa B p50和p65亚基的蛋白水平升高以及抑制剂I kappa B α的显著磷酸化/降解有关。在结肠损伤的动物中，STAT1、STAT5和Akt磷酸化形式的蛋白水平升高。所有这些作用均被谷氨酰胺抑制。在谷氨酰胺处理的动物中，TNBS灌注48小时后，细胞内TBARS浓度、氢过氧化物引发的化学发光、氧化应激标志物以及肿瘤坏死因子α (TNF α)和干扰素γ (IFN γ)水平的升高均被显著抑制。结论：抑制NF-kappa B和STAT信号通路调控的促炎介质的表达参与了谷氨酰胺对实验性结肠炎TNBS模型的治疗作用。这些作用可能是通过抑制氧化应激和减少促炎细胞因子的表达来实现的。
Background: We investigated the effects of glutamine on proinflammatory gene expression and activation of nuclear factor kappa B (NF-kappa B) and signal transducers and activators of transcription (STAT) in a rat model of experimental colitis.Methods: Colitis was induced in male Wistar rats by intracolonic administration of 30 mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Glutamine (25 mg/kg) was given by rectal route daily for 7 days.Results: Glutamine significantly reduced gross damage and histopathological scores and prevented the decrease of anal pressure and the elevated myeloperoxidase activity observed in the colon of animals receiving TNBS. TNBS administration induced a marked increase of vascular cell adhesion molecule (VCAM-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) protein levels. These inflammatory events were associated with increased protein level of NF-kappa B p50 and p65 subunits in the nucleus and significant phosphorylation/degradation of the inhibitor I kappa B alpha. Protein levels of the phosphorylated forms of STAT1, STAT5, and Akt were elevated in animals with colonic damage. All these effects were inhibited by administration of glutamine. Increases in the cytosolic concentration of TBARS and hydroperoxide-initiated chemiluminescence, markers of oxidative stress, and levels of tumor necrosis factor alpha(TNF alpha) and interferon gamma (IFN gamma) were significantly inhibited at 48 hours of TNBS instillation in glutamine-treated animals.Conclusions: Inhibition of the expression of proinflammatory mediators that are regulated by the NF-kappa B and STAT signaling pathways contribute to the therapeutical effect of glutamine in the TNBS model of experimental colitis. These effects may be brought about by inhibition of oxidative stress and reduced expression of proinflammatory cytokines.