Marafini Irene, Di Fusco Davide, Dinallo Vincenzo, Franzè Eleonora, Stolfi Carmine, Sica Giuseppe, Monteleone Giovanni, Monteleone Ivan
Department of Systems Medicine, Gastroenterology, University of Tor Vergata, Rome, Italy.
Department of Surgery, University of Tor Vergata, Rome, Italy.
Front Pharmacol. 2019 Apr 12;10:380. doi: 10.3389/fphar.2019.00380. eCollection 2019.
Defects in counterregulatory mechanisms contribute to amplify the detrimental inflammatory response leading to the pathologic process occurring in the gut of patients with Crohn's disease (CD) and ulcerative colitis (UC), the major inflammatory bowel diseases (IBDs), in human beings. One such mechanism involves aryl hydrocarbon receptor (AhR), a transcription factor activated by natural and synthetic ligands, which induces the production of interleukin (IL)-22 and down-regulates inflammatory signals. In IBD, AhR expression is down-regulated and its activation by natural ligands promotes clinical and endoscopic benefit. Since the use of AhR natural ligands can associate with serious adverse events, we developed new chemical ligands of AhR and assessed their regulatory effects. Among these derivatives, we selected the compounds NPD-0414-2 and NPD-0414-24, as they displayed the more pronounced capacity to induce IL-22. Peripheral blood mononuclear cells and lamina propria mononuclear cells (LPMC) were isolated from CD and UC patients. Cells were treated with Ficz, AhR ligands, and AhR antagonist and then cytokines' expression was evaluated by real-time PCR and flow cytometry. After the induction of TNBS colitis, Ficz and AhR ligands were injected intra-peritoneally to wild type and AhR knock-out mice. After 4 days, mice were sacrificed and colonic tissues were collected for histologic examination and real-time PCR analysis. Treatment of IBD LPMC with NPD-0414-2 and NPD-0414-24 reduced IFN-γ and increased IL-22 transcripts, and these effects were abrogated by CH223191, a specific inhibitor of AhR interaction with its ligands. Mice given NPD-0414-2 and NPD-0414-24 developed a significantly less severe form of TNBS colitis and exhibited reduced expression of IFN-γ and increased expression of IL-22. The therapeutic effect of NPD-0414-2 and NPD-0414-24 on the ongoing colitis was abrogated in AhR-deficient mice. Collectively, these data show that NPD-0414-2 and NPD-0414-24 exert Ahr-dependent regulatory effects in the gut.
负反馈调节机制的缺陷会加剧有害的炎症反应，从而导致人类主要炎症性肠病（IBD），即克罗恩病（CD）和溃疡性结肠炎（UC）患者肠道中发生的病理过程。其中一种机制涉及芳烃受体（AhR），它是一种由天然和合成配体激活的转录因子，可诱导白细胞介素（IL）-22的产生并下调炎症信号。在IBD中，AhR表达下调，其被天然配体激活可带来临床和内镜方面的益处。由于使用AhR天然配体可能会引发严重不良事件，我们开发了新的AhR化学配体并评估了它们的调节作用。在这些衍生物中，我们选择了化合物NPD-0414-2和NPD-0414-24，因为它们诱导IL-22的能力更为显著。从CD和UC患者中分离出外周血单核细胞和固有层单核细胞（LPMC）。用Ficz、AhR配体和AhR拮抗剂处理细胞，然后通过实时PCR和流式细胞术评估细胞因子的表达。诱导TNBS结肠炎后，将Ficz和AhR配体腹腔注射到野生型和AhR基因敲除小鼠体内。4天后，处死小鼠并收集结肠组织进行组织学检查和实时PCR分析。用NPD-0414-2和NPD-0414-24处理IBD LPMC可降低IFN-γ水平并增加IL-22转录本，而这些作用被CH223191（一种AhR与其配体相互作用的特异性抑制剂）消除。给予NPD-0414-2和NPD-0414-24的小鼠发生的TNBS结肠炎严重程度明显减轻，且IFN-γ表达降低，IL-22表达增加。在AhR缺陷小鼠中，NPD-0414-2和NPD-0414-24对正在进行的结肠炎的治疗作用被消除。总的来说，这些数据表明NPD-0414-2和NPD-0414-24在肠道中发挥AhR依赖性调节作用。
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