A partial agonist for retinoid X receptor mitigates experimental colitis
A partial agonist for retinoid X receptor mitigates experimental colitis
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DOI：
10.1093/intimm/dxy089
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发表时间：
2019-04-01
影响因子：
4.4
通讯作者：
Hase, Koji
中科院分区：
文献类型：
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作者：
Onuki, Masayoshi;Watanabe, Masaki;Hase, Koji
炎症性肠病（IBD）包括溃疡性结肠炎和克罗恩病，是一种难治性胃肠道疾病。包括食物成分在内的多种环境因素与这些疾病的发展有关。例如，富含动物脂肪的饮食是溃疡性结肠炎的诱发因素，而n-3不饱和脂肪酸如二十二碳六烯酸（DHA）在实验性结肠炎中显示出保护作用，并与溃疡性结肠炎和克罗恩病的发病率呈负相关。鉴于DHA对类维生素A X受体（RXR）表现出激动活性，RXR的激活可能是IBD的治疗策略。然而，已知常规的完全RXR激动剂显示出相当大的副作用。因此，我们利用部分RXR激动剂，CBt-PMN，以尽量减少不良反应，并评估其在葡聚糖硫酸钠诱导的结肠炎的疗效。给予CBt-PMN有效地改善了结肠炎的症状。这种作用归因于结肠浸润单核细胞中促炎细胞因子如TNF和IL 6的下调。CBt-PMN对促炎细胞因子的下调在脂多糖刺激的骨髓源性巨噬细胞（BMDM）中也很明显。在许多RXR相关的核受体中，过氧化物酶体增殖物激活受体（PPAR）和核激素受体77（Nur 77）的激活抑制了BMDM细胞因子的产生。这些观察结果表明，CBt-PMN通过许可机制激活PPAR/RXR和Nur 77/RXR异源二聚体是减少肠道中单核细胞介导的炎症反应的原因。我们的数据强调了RXR激活在调节结肠炎中的重要性。部分RXR激动剂在改善结肠炎的同时减少副作用
Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is an intractable disease of the gastrointestinal tract. Multiple environmental factors, including food ingredients, have been implicated in the development of these diseases. For example, animal fat-rich diets are predisposing factors for ulcerative colitis, whereas n-3 unsaturated fatty acids such as docosahexaenoic acid (DHA) show protective effects in experimental colitis and are negatively correlated with the incidence of ulcerative colitis and Crohn's disease. Given that DHA exhibits agonistic activity on retinoid X receptor (RXR), activation of RXR could be a therapeutic strategy for IBD. However, conventional full RXR agonists are known to show considerable adverse effects. We therefore took advantage of a partial RXR agonist, CBt-PMN, to minimize the adverse effects, and evaluated its efficacy in dextran sodium sulfate-induced colitis. Administration of CBt-PMN efficiently ameliorated the symptoms of colitis. This effect was attributed to the down-regulation of pro-inflammatory cytokines such as Tnf and Il6 in colon-infiltrating monocytes. Down-regulation of pro-inflammatory cytokines by CBt-PMN was also evident in lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDMs). Among many RXR-associated nuclear receptors, activation of peroxisome proliferator-activated receptor (PPAR) and nuclear hormone receptor 77 (Nur77) suppressed cytokine production by BMDMs. These observations suggest that the activation of PPAR/RXR and Nur77/RXR heterodimers by CBt-PMN through the permissive mechanism is responsible for diminishing the monocyte-mediated inflammatory response in the gut. Our data highlight the importance of RXR activation in the regulation of colitis.A partial RXR agonist reduces side-effects while ameliorating colitis