Cominelli F, Dinarello C A
Division of Gastroenterology, Harbor-UCLA Medical Center, Torrance.
Biotherapy. 1989;1(4):369-75. doi: 10.1007/BF02171013.
Inflammatory bowel disease affects millions of people, some with fatal consequences. Little is known about the factors which contribute to its pathogenesis particularly regarding cytokine production and action. In this paper we summarize our recent findings using the rabbit model for immune complex-generated experimental colitis, a model which is similar to ulcerative colitis in humans. Recombinant human IL-1 was perfused through rabbit colons and we observed elevated levels of PGE2, TxB2 and 6-keto-PGF1 alpha, the stable metabolite of PGI2. Using radioimmunoassays specific for rabbit IL-1 alpha and IL-1 beta, we induced immune complex colitis and measured the generation of these IL-1's in various tissues. Markedly elevated levels of IL-1 were detected only in inflamed tissues. The levels of IL-1 correlated with the degree of inflammation as judged by a blinded assessment of pathological changes. Similar to other disease models in which small doses of the agonist can afford protection or result in a state of "desensitization" when administered prior to the onset of the disease, we accordingly injected rabbits with a single, small (300 ng/kg) dose of IL-1 and observed a significant reduction in the inflammatory index and necrosis of immune complex colitis. However, unlike other models of IL-1-induced protection, in this model cyclooxygenase products were required since we prevented the IL-1-induced protection with a single dose of ibuprofen given at the same time as the IL-1. This correlated with the reduction in IL-1-induced PGE2. These results demonstrate that IL-1 plays a key role in the pathogenesis of inflammatory bowel disease in the rabbit and that the protection afforded by a low dose of IL-1 24 hours before the onset of the colitis requires IL-1-induced cyclooxygenase products.
炎症性肠病影响着数百万人，其中一些会导致致命后果。对于导致其发病机制的因素，尤其是细胞因子的产生和作用，人们了解甚少。在本文中，我们总结了我们最近使用兔免疫复合物诱导的实验性结肠炎模型所获得的研究结果，该模型与人类溃疡性结肠炎相似。将重组人白细胞介素 -1 灌注到兔结肠中，我们观察到前列腺素E2、血栓素B2和前列环素（PGI2）的稳定代谢产物6 - 酮 - 前列环素F1α水平升高。使用针对兔白细胞介素 -1α和白细胞介素 -1β的放射免疫分析法，我们诱导了免疫复合物性结肠炎，并测量了这些白细胞介素 -1在各种组织中的生成情况。仅在发炎组织中检测到白细胞介素 -1水平显著升高。通过对病理变化的盲法评估判断，白细胞介素 -1水平与炎症程度相关。与其他疾病模型相似，在这些模型中，小剂量的激动剂在疾病发作前给药可提供保护或导致“脱敏”状态，因此我们给兔子注射了单次小剂量（300 ng/kg）的白细胞介素 -1，并观察到免疫复合物性结肠炎的炎症指数和坏死显著降低。然而，与其他白细胞介素 -1诱导保护的模型不同，在该模型中需要环氧化酶产物，因为我们在给予白细胞介素 -1的同时给予单剂量布洛芬可阻止白细胞介素 -1诱导的保护作用。这与白细胞介素 -1诱导的前列腺素E2减少相关。这些结果表明，白细胞介素 -1在兔炎症性肠病的发病机制中起关键作用，并且在结肠炎发作前24小时给予低剂量白细胞介素 -1所提供的保护作用需要白细胞介素 -1诱导的环氧化酶产物。
