Differential regulation of interleukin 17 and interferon γ production in inflammatory bowel disease
Differential regulation of interleukin 17 and interferon γ production in inflammatory bowel disease
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DOI：
10.1136/gut.2009.182170
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发表时间：
2009-12-01
期刊：
影响因子：
24.5
通讯作者：
MacDonald, T. T.
中科院分区：
文献类型：
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作者：
Rovedatti, L.;Kudo, T.;MacDonald, T. T.
背景和目的：目前已知白细胞介素 17 (IL17) 与许多慢性炎症性疾病有关。然而，在炎症性肠病（IBD）中调节其产生的机制仍不清楚。 方法：从 72 名 IBD 患者（38 名克罗恩病患者和 34 名溃疡性结肠炎患者）的发炎和未发炎结肠粘膜以及 38 名对照受试者的正常结肠中采集内窥镜活检或手术标本。通过 ELISA 检测体外培养的活检组织上清液中的 IL17 和干扰素 γ (IFN γ)，以及与 IL12、IL23、IL1b 加 IL6、转化生长因子 β 1 (TGF β 1) 或抗 IL21 中和抗体一起孵育的抗 CD3/CD28 刺激的固有层单核细胞 (LPMC) 上清液中的 IL17 和干扰素 γ (IFN γ)。采用细胞内流式细胞术分析粘膜 Th17 和 Th1/Th17 细胞。结果：IBD 发炎粘膜中器官培养活检产生的 IL17 高于 IBD 未发炎粘膜和对照，且与 IFN γ 的量相当。与对照相比，抗 CD3/CD28 刺激的 IBD LPMC 产生更高的 IL17 量。 IBD 患者的 Th17 和 Th1/Th17 细胞百分比增加。 IL23和IL1β加IL6对IBD LPMC产生IL17没有影响；然而，IL12 显着增加 IFN γ 的产生并减少 IL17 的产生。 TGFβ1剂量依赖性地降低IFNγ，但对IL17的产生没有显着的抑制作用。阻断 IL21 显着下调 IL17 的产生。结论：我们的研究结果支持 IL12、TGF β 和 IL21 在调节 IBD 中 IL17/IFN γ 产生中的作用。发炎的 IBD 粘膜中丰富的 IL17 可能有助于解释抗 IFN γ 抗体在克罗恩病临床试验中相对缺乏疗效的原因。
Background and Aims: Interleukin 17 (IL17) is now known to be involved in a number of chronic inflammatory disorders. However, the mechanisms regulating its production in inflammatory bowel disease (IBD) are still unclear.Methods: Endoscopic biopsies or surgical specimens were taken from inflamed and uninflamed colonic mucosa of 72 patients with IBD (38 with Crohn's disease and 34 with ulcerative colitis), and normal colon of 38 control subjects. IL17 and interferon gamma (IFN gamma) were detected by ELISA in the supernatants of biopsies cultured ex vivo, and anti-CD3/CD28-stimulated lamina propria mononuclear cells (LPMCs) incubated with IL12, IL23, IL1b plus IL6, transforming growth factor beta 1 (TGF beta 1), or anti-IL21 neutralising antibody. Intracellular flow cytometry was performed to analyse mucosal Th17 and Th1/Th17 cells.Results: IL17 production by organ culture biopsies was higher in IBD inflamed mucosa than IBD uninflamed mucosa and controls, and was equivalent in amount to IFN gamma. Anti-CD3/CD28-stimulated IBD LPMCs produced higher IL17 amounts compared to controls. The percentages of Th17 and Th1/Th17 cells were increased in patients with IBD. IL23 and IL1 beta plus IL6 had no effect on IBD LPMC production of IL17; however, IL12 markedly increased IFN gamma production and decreased IL17 production. TGF beta 1 dose-dependently decreased IFN gamma, but had no significant inhibitory effect on IL17 production. Blocking IL21 significantly downregulated IL17 production.Conclusions: Our findings support a role for IL12, TGF beta and IL21 in modulating IL17/IFN gamma production in IBD. The abundant IL17 in inflamed IBD mucosa may help explain the relative lack of efficacy of anti-IFN gamma antibodies in clinical trials of Crohn's disease.