BACKGROUND Recent works provide evidence of the importance of the prostaglandin D2 (PGD2) metabolic pathway in inflammatory bowel diseases. We investigated the expression of PGD2 metabolic pathway actors in Crohn's disease (CD) and the ability of the enteric nervous system (ENS) to produce PGD2 in inflammatory conditions. METHODS Expression of key actors involved in the PGD2 metabolic pathway and its receptors was analyzed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in colonic mucosal biopsies of patients from three groups: controls, quiescent and active CD patients. To determine the ability of the ENS to secrete PGD2 in proinflammatory conditions, Lipocalin-type prostaglandin D synthase (L-PGDS) expression by neurons and glial cells was analyzed by immunostaining. PGD2 levels were determined in a medium of primary culture of ENS and neuro-glial coculture model treated by lipopolysaccharide (LPS). RESULTS In patients with active CD, inflamed colonic mucosa showed significantly higher COX2 and L-PGDS mRNA expression, and significantly higher PGD2 levels than healthy colonic mucosa. On the contrary, peroxysome proliferator-activated receptor Gamma (PPARG) expression was reduced in inflamed colonic mucosa of CD patients with active disease. Immunostaining showed that L-PGDS was expressed in the neurons of human myenteric and submucosal plexi. A rat ENS primary culture model confirmed this expression. PGD2 levels were significantly increased on primary culture of ENS treated with LPS. This production was abolished by AT-56, a specific competitive L-PGDS inhibitor. The neuro-glial coculture model revealed that each component of the ENS, ECG and neurons, could contribute to PGD2 production. CONCLUSIONS Our results highlight the activation of the PGD2 metabolic pathway in Crohn's disease. This study supports the hypothesis that in Crohn's disease, enteric neurons and glial cells form a functional unit reacting to inflammation by producing PGD2.

中文翻译：

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克罗恩病中前列腺素D2代谢途径的激活：肠神经系统受累。

背景技术最近的研究提供了前列腺素D2（PGD2）代谢途径在炎性肠病中的重要性的证据。我们调查了PGD2代谢途径演员在克罗恩病（CD）中的表达和肠道神经系统（ENS）在炎性条件下产生PGD2的能力。方法使用定量逆转录酶聚合酶链反应（qRT-PCR）分析了三组患者结肠黏膜活检中PGD2代谢途径及其受体的关键因子的表达：对照组，静止期和活动性CD患者。为了确定ENS在促炎条件下分泌PGD2的能力，通过免疫染色分析了神经元和神经胶质细胞表达的Lipocalin型前列腺素D合酶（L-PGDS）。在ENS的原代培养培养基和脂多糖（LPS）处理的神经胶质共培养模型中确定PGD2的水平。结果在具有活动性CD的患者中，发炎的结肠粘膜显示出比健康的结肠粘膜显着更高的COX2和L-PGDS mRNA表达，以及显着更高的PGD2水平。相反，在患有活动性疾病的CD患者的发炎的结肠粘膜中，过氧化物酶体增殖物激活的受体Gamma（PPARG）表达降低。免疫染色显示，L-PGDS在人的肠系膜和粘膜下丛神经元中表达。大鼠ENS原代培养模型证实了这一表达。在LPS处理的ENS的原代培养中，PGD2水平显着增加。该生产被竞争性L-PGDS抑制剂AT-56取消。神经胶质细胞共培养模型表明，ENS，ECG和神经元的每个成分都可以促进PGD2的产生。结论我们的结果突出了克罗恩病中PGD2代谢途径的激活。这项研究支持以下假说：在克罗恩氏病中，肠神经元和神经胶质细胞形成功能性单位，通过产生PGD2对炎症做出反应。