Aryl Hydrocarbon Receptor-Induced Signals Up-regulate IL-22 Production and Inhibit Inflammation in the Gastrointestinal Tract
Aryl Hydrocarbon Receptor-Induced Signals Up-regulate IL-22 Production and Inhibit Inflammation in the Gastrointestinal Tract
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DOI：
10.1053/j.gastro.2011.04.007
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发表时间：
2011-07-01
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：
Monteleone, Ivan;Rizzo, Angelamaria;Monteleone, Giovanni
背景与目的：炎症性肠病（IBD）的发病机制被认为涉及效应和调节T细胞之间的平衡改变。芳烃受体（AhR）是一种介导二恶英毒性的配体依赖性转录因子，控制T细胞反应。我们在人类和小鼠模型中研究了AhR在炎症和IBD发病机制中的作用。方法：通过实时聚合酶链反应（PCR）和流式细胞术评估IBD患者和对照组肠组织样本中AhR的表达。在存在或不存在AhR激动剂6-甲酰吲哚并（3，2-B）咔唑（Ficz）的情况下激活肠固有层单核细胞（LPMC）。使用三硝基苯磺酸（TNBS）、葡聚糖硫酸钠（DSS）或T细胞转移在小鼠中诱导结肠炎。给小鼠注射Ficz或AhR拮抗剂2-甲基-2H-吡唑-3-羧酸;一些小鼠首先接受针对白细胞介素（IL）-22的阻断抗体的注射。通过实时PCR和流式细胞术定量细胞因子。结果：IBD患者的肠组织表达的AhR显著低于对照组。在来自IBD患者的LPMC中，与Ficz孵育降低了干扰素γ（IFN）-γ的水平并上调了IL-22。注射Ficz的小鼠受到保护，免受TNBS、DSS和T细胞转移诱导的结肠炎的影响;它们具有显著的炎性细胞因子下调和IL-22诱导。给予AhR拮抗剂的小鼠产生更多的炎性细胞因子和更少的IL-22，并发展成严重的结肠炎。内源性IL-22的中和破坏了Ficz对TNBS诱导的结肠炎的保护作用。结论：AhR在IBD患者的肠组织中下调; AhR信号通过IL-22抑制小鼠胃肠道中的炎症和结肠炎。AhR相关化合物可能被开发用于治疗IBD患者。
BACKGROUND & AIMS: The pathogenesis of inflammatory bowel disease (IBD) is believed to involve an altered balance between effector and regulatory T cells. Aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor that mediates the toxicity of dioxins, controls T-cell responses. We investigated the role of AhR in inflammation and pathogenesis of IBD in humans and mouse models. METHODS: AhR expression was evaluated in intestinal tissue samples from patients with IBD and controls by real-time polymerase chain reaction (PCR) and flow cytometry. Intestinal lamina propria mononuclear cells (LPMCs) were activated in the presence or absence of the AhR agonist 6-formylindolo(3, 2-b)carbazole (Ficz). Colitis was induced in mice using trinitrobenzene sulfonic acid (TNBS), dextran sulfate sodium (DSS), or T-cell transfer. Mice were given injections of Ficz or the AhR antagonist 2-metyl-2H-pyrazole-3-carboxylic acid; some mice first received injections of a blocking antibody against interleukin (IL)-22. Cytokines were quantified by real-time PCR and flow cytometry. RESULTS: Intestine tissue from patients with IBD expressed significantly less AhR than controls. In LPMCs from patients with IBD, incubation with Ficz reduced levels of interferon gamma (IFN)-gamma and up-regulated IL-22. Mice injected with Ficz were protected against TNBS-, DSS-, and T-cell transfer-induced colitis; they had marked down-regulation of inflammatory cytokines and induction of IL-22. Mice given AhR antagonist produced more inflammatory cytokines and less IL-22 and developed a severe colitis. Neutralization of endogenous IL-22 disrupted the protective effect of Ficz on TNBS- induced colitis. CONCLUSIONS: AhR is down-regulated in intestinal tissue of patients with IBD; AhR signaling, via IL-22, inhibits inflammation and colitis in the gastrointestinal tract of mice. AhR-related compounds might be developed to treat patients with IBDs.