Rovedatti L, Kudo T, Biancheri P, Sarra M, Knowles C H, Rampton D S, Corazza G R, Monteleone G, Di Sabatino A, Macdonald T T
Institute of Cell and Molecular Science, London School of Medicine and Dentistry, London E1 2AT, UK.
Gut. 2009 Dec;58(12):1629-36. doi: 10.1136/gut.2009.182170. Epub 2009 Sep 8.
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.
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 (IFNgamma) 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, IL1beta plus IL6, transforming growth factor beta1 (TGFbeta1), or anti-IL21 neutralising antibody. Intracellular flow cytometry was performed to analyse mucosal Th17 and Th1/Th17 cells.
IL17 production by organ culture biopsies was higher in IBD inflamed mucosa than IBD uninflamed mucosa and controls, and was equivalent in amount to IFNgamma. 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 IL1beta plus IL6 had no effect on IBD LPMC production of IL17; however, IL12 markedly increased IFNgamma production and decreased IL17 production. TGFbeta1 dose-dependently decreased IFNgamma, but had no significant inhibitory effect on IL17 production. Blocking IL21 significantly downregulated IL17 production.
Our findings support a role for IL12, TGFbeta and IL21 in modulating IL17/IFNgamma production in IBD. The abundant IL17 in inflamed IBD mucosa may help explain the relative lack of efficacy of anti-IFNgamma antibodies in clinical trials of Crohn's disease.
白细胞介素17（IL17）现已被证实参与多种慢性炎症性疾病。然而，炎症性肠病（IBD）中调节其产生的机制仍不清楚。
从72例IBD患者（38例克罗恩病患者和34例溃疡性结肠炎患者）的炎症性和非炎症性结肠黏膜以及38例对照受试者的正常结肠获取内镜活检组织或手术标本。通过酶联免疫吸附测定法（ELISA）检测体外培养的活检组织上清液以及与IL12、IL23、IL1β加IL6、转化生长因子β1（TGFβ1）或抗IL21中和抗体孵育的抗CD3/CD28刺激的固有层单核细胞（LPMC）中的IL17和干扰素γ（IFNγ）。进行细胞内流式细胞术分析黏膜Th17和Th1/Th17细胞。
IBD炎症性黏膜中器官培养活检组织产生的IL17高于IBD非炎症性黏膜和对照，且其产量与IFNγ相当。与对照相比，抗CD3/CD28刺激的IBD LPMC产生的IL17量更高。IBD患者中Th17和Th1/Th17细胞的百分比增加。IL23和IL1β加IL6对IBD LPMC产生IL17没有影响；然而，IL12显著增加IFNγ的产生并降低IL17的产生。TGFβ1剂量依赖性地降低IFNγ，但对IL17的产生没有显著抑制作用。阻断IL21可显著下调IL17的产生。
我们的研究结果支持IL12、TGFβ和IL21在调节IBD中IL17/IFNγ产生方面的作用。IBD炎症黏膜中丰富的IL17可能有助于解释抗IFNγ抗体在克罗恩病临床试验中相对缺乏疗效的原因。
