Hogaboam C M, Vallance B A, Kumar A, Addison C L, Graham F L, Gauldie J, Collins S M
Intestinal Disease Research Programme, McMaster University, Hamilton, Ontario, Canada.
J Clin Invest. 1997 Dec 1;100(11):2766-76. doi: 10.1172/JCI119823.
Inflammatory bowel disease (IBD) is characterized by altered immunoregulation and augmented intestinal synthesis of nitric oxide. The purpose of this study was to determine the effects of exogenous IL-4, introduced by a recombinant human type 5 adenovirus (Ad5) vector, on the tissue injury associated with an experimental model of colonic immune activation and inflammation. Colitis was induced in rats by the intrarectal administration of trinitrobenzene sulfonic acid (TNB) dissolved in 50% ethanol, and control rats received saline via the same route. 1 h later, all rats were randomized into two groups. The first group was injected intraperitoneally (ip) with 3.0 x 10(6) plaque forming units (PFUs) of Ad5 transfected with murine interleukin-4 (Ad5IL-4) and the second group was injected ip with the same amount of Ad5 expressing the Escherichia coli Lac Z gene (Ad5LacZ). One-half of the colitic and control rats were injected again with 3.0 x 10(6) PFUs of Ad5IL-4 or Ad5LacZ on day 3 of the 6-d study. When introduced once or twice via the peritoneal route into control rats, Ad5LacZ was localized to the serosal lining of the peritoneal cavity, the diaphragm and the liver on day 6. One or two injections of Ad5IL-4 into rats also produced measurable levels of circulating IL-4. TNB-colitis in both Ad5LacZ-treated groups was associated with pronounced elevations in serum IFN-gamma, and mucosal ulceration of the distal colon. Myeloperoxidase and inducible nitric oxide synthase II (NOS II) synthetic activity were also increased by 30- and fivefold, respectively, above control levels in the distal colon. However, two injections of Ad5IL-4 into colitic rats caused the overexpression of IL-4, and significantly inhibited tissue damage, serum and colon IFN-gamma levels and myeloperoxidase activity in the distal colon. In addition, NOS II gene expression and NOS II nitric oxide synthesis was significantly inhibited. No therapeutic effect was observed in rats injected once with Ad5IL-4. Thus, IL-4, introduced by Ad5, is therapeutic during acute inflammation in the rat colon. The therapeutic effect of IL-4 was associated with an inhibition of inducible nitric oxide expression and a reduction in nitric oxide synthesis.
炎症性肠病（IBD）的特征是免疫调节改变和肠道一氧化氮合成增加。本研究的目的是确定由重组人5型腺病毒（Ad5）载体导入的外源性白细胞介素-4（IL-4）对与结肠免疫激活和炎症实验模型相关的组织损伤的影响。通过直肠内给予溶解于50%乙醇中的三硝基苯磺酸（TNB）诱导大鼠结肠炎，对照大鼠通过相同途径接受生理盐水。1小时后，将所有大鼠随机分为两组。第一组腹腔内注射（ip）3.0×10⁶ 个转染了小鼠白细胞介素-4的Ad5噬斑形成单位（PFU）（Ad5IL-4），第二组腹腔内注射等量表达大肠杆菌Lac Z基因的Ad5（Ad5LacZ）。在为期6天的研究的第3天，将一半的结肠炎大鼠和对照大鼠再次注射3.0×10⁶ PFU的Ad5IL-4或Ad5LacZ。当通过腹腔途径向对照大鼠注射一次或两次Ad5LacZ时，在第6天Ad5LacZ定位于腹膜腔的浆膜层、膈肌和肝脏。向大鼠注射一或两次Ad5IL-4也产生了可测量水平的循环IL-4。两个Ad5LacZ处理组的TNB结肠炎均伴有血清干扰素-γ明显升高以及远端结肠黏膜溃疡。远端结肠中的髓过氧化物酶和诱导型一氧化氮合酶II（NOS II）合成活性也分别比对照水平增加了30倍和5倍。然而，向结肠炎大鼠注射两次Ad5IL-4导致IL-4过度表达，并显著抑制了组织损伤、血清和结肠干扰素-γ水平以及远端结肠中的髓过氧化物酶活性。此外，NOS II基因表达和NOS II一氧化氮合成受到显著抑制。单次注射Ad5IL-4的大鼠未观察到治疗效果。因此，由Ad5导入的IL-4在大鼠结肠急性炎症期间具有治疗作用。IL-4的治疗作用与诱导型一氧化氮表达的抑制和一氧化氮合成的减少有关。
