Regulation of gut inflammation and Th17 cell response by interleukin-21
Regulation of gut inflammation and Th17 cell response by interleukin-21
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DOI：
10.1053/j.gastro.2008.01.041
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发表时间：
2008-04-01
期刊：
影响因子：
29.4
通讯作者：
Monteleone, Giovanni
中科院分区：
文献类型：
--
作者：
Fina, Daniele;Sarra, Massimiliano;Monteleone, Giovanni
背景和目标：白细胞介素（IL）-21是一种T细胞衍生的细胞因子，在炎症性肠病中过度产生（1111），但其在肠道炎症发病机制中的作用仍不清楚。我们在这里研究了IL-21是否是实验性结肠炎的开始和进展所必需的，以及它是否调节炎症的特定途径。方法：在野生型和IL-21缺陷小鼠中诱导葡聚糖硫酸钠结肠炎和三硝基苯磺酸复发性结肠炎。来自野生型和IL-21缺陷型小鼠的CD 4（+）CD 25（-）T细胞在T辅助细胞（Th）17极化条件下分化，有或没有IL-21或拮抗性IL-21 R/Fc。我们还检测了在IBD固有层CD 3（+）T淋巴细胞培养物中，抗IL-21抗体阻断IL-21是否会降低IL-17。通过实时聚合酶链反应和/或酶联免疫吸附试验评价细胞因子。结果：在葡聚糖硫酸钠和三硝基苯磺酸复发性结肠炎的野生型小鼠中观察到高IL-21。IL-21缺陷小鼠在很大程度上受到保护，免受两种大肠杆菌肽的侵害，并且在肠道炎症期间无法上调Th 17相关分子，因此表明IL-21在控制Th 17细胞应答中的作用。事实上，来自IL-21缺陷小鼠的初始T细胞未能分化成Th 17细胞。用IL-21 R/Fc处理来自野生型小鼠的发育中的Th 17细胞减少了IL-17的产生。此外，在转化生长因子β 1存在下，外源性IL-21取代IL-6驱动IL-17诱导。IL-21的中和减少IBD固有层淋巴细胞的IL-17分泌。结论：这些结果表明，IL-21是肠道炎症和Th 17细胞反应的关键调节因子。
Background & Aims: Interleukin (IL)-21, a T-cell-derived cytokine, is overproduced in inflammatory bowel diseases (1111)), but its role in the pathogenesis of gut inflammation remains unknown. We here examined whether IL-21 is necessary for the initiation and progress of experimental colitis and whether it regulates specific pathways of inflammation. Methods: Both dextran sulfate sodium colitis and trinitrobenzene sulfonic acid-relapsing colitis were induced in wild-type and IL-21-deficient mice. CD4(+)CD25(-) T cells from wild-type and IL-21-deficient mice were differentiated in T helper cell (Th) 17-polarizing conditions, with or without IL-21 or an antagonistic IL-21R/Fc. We also examined whether blockade of IL-21 by anti-IL-21 antibody reduced IL-17 in cultures of IBD lamina propria CD3(+) T lymphocytes. Cytokines were evaluated by real-time polymerase chain reaction and/or enzyme-linked immunosorbent assay. Result : High IL-21 was seen in wild-type mice with dextran sulfate sodium- and trinitrobenzene sulfonic acid-relapsing colitis. IL-21-deficient mice were largely protected against both colitides and were unable to up-regulate Th17-associated molecules during gut inflammation, thus suggesting a role for IL-21 in controlling Th17 cell responses. Indeed, naive T cells from IL-21-deficient mice failed to differentiate into Th17 cells. Treatment of developing Th17 cells from wild-type mice with IL-21R/Fc reduced IL-17 production. Moreover, in the presence of transforming growth factor-beta 1, exogenous IL-21 substituted for IL-6 in driving IL-17 induction. Neutralization of IL-21 reduced IL-17 secretion by IBD lamina propria lymphocytes. Conclusions: These results indicate that IL-21 is a critical regulator of inflammation and Th17 cell responses in the gut.