Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
Inflamm Bowel Dis. 2010 Aug;16(8):1332-9. doi: 10.1002/ibd.21238.
We previously demonstrated that in inflammatory bowel disease (IBD) there is enhanced production of interleukin (IL)-21, a cytokine that activates multiple pathways that sustain mucosal inflammation. However, the phenotype of IL-21-producing cells in IBD, and the cytokine(s) they coproduce, is not known. We here characterized the cell source of IL-21 and determined which factors regulate IL-21 in the human gut.
Cytokines were analyzed in CD4+ T intestinal lamina propria lymphocytes (T-LPL) isolated from IBD patients and controls by flow cytometry. Moreover, IL-21 was evaluated in mucosal T follicular cells (TFH). To assess the involvement of IL-12 and IL-23 in the production of IL-21, T-LPL were activated in the presence or absence of IL-12 or IL-23.
The proportion of IL-21-producing CD4+ T-LPL was increased in IBD compared to controls. The majority of IL-21-producing T-LPL coexpressed interferon (IFN)-gamma, and to a lesser extent IL-4 or IL-17A. Activation of CD4+ T-LPL with IL-12 but not IL-23 enhanced the fraction of cells coexpressing IL-21 and IFN-gamma. TFH cells in LPL were identified by CXCR5 expression and expressed IL-21 both in IBD and controls; however, the fraction of IL-21-positive TFH cells was higher in Crohn's disease than in ulcerative colitis and controls. Treatment of CD4+ T-LPL with IL-12 enhanced the frequency of CXCR5+ IL-21-producing TFH cells.
These findings indicate that in IBD IL-21 is mostly produced by CD4+ T-LPL coexpressing IFN-gamma, reinforcing the concept that distinct subsets of T cells can produce IL-21.
我们之前的研究表明，在炎症性肠病（IBD）中，白细胞介素（IL）-21 的产生增加，这种细胞因子可激活多种维持黏膜炎症的途径。然而，IBD 中产生 IL-21 的细胞表型及其共产生的细胞因子尚不清楚。本研究旨在描述 IL-21 产生细胞的来源，并确定哪些因素调节人类肠道中的 IL-21。
通过流式细胞术分析 IBD 患者和对照者肠道黏膜固有层 CD4+T 淋巴细胞（T-LPL）中的细胞因子。此外，评估黏膜滤泡辅助性 T 细胞（TFH）中的 IL-21。为了评估 IL-12 和 IL-23 在 IL-21 产生中的作用，T-LPL 在存在或不存在 IL-12 或 IL-23 的情况下被激活。
与对照组相比，IBD 患者的 IL-21 产生 CD4+T-LPL 的比例增加。大多数产生 IL-21 的 T-LPL 共表达干扰素（IFN）-γ，其次是 IL-4 或 IL-17A。用 IL-12 而非 IL-23 激活 CD4+T-LPL 可增强共表达 IL-21 和 IFN-γ的细胞比例。通过 CXCR5 表达鉴定 LPL 中的 TFH 细胞，并在 IBD 和对照组中均表达 IL-21；然而，克罗恩病中 IL-21 阳性 TFH 细胞的比例高于溃疡性结肠炎和对照组。用 IL-12 处理 CD4+T-LPL 可增加 CXCR5+IL-21 产生 TFH 细胞的频率。
这些发现表明，在 IBD 中，IL-21 主要由共表达 IFN-γ的 CD4+T-LPL 产生，这进一步证实了不同的 T 细胞亚群可以产生 IL-21。
