Interleukin-33 delays recovery of mucosal inflammation via downregulation of homeostatic ABCG5/8 in the colon
Interleukin-33 delays recovery of mucosal inflammation via downregulation of homeostatic ABCG5/8 in the colon
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DOI：
10.1038/s41374-019-0329-3
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发表时间：
2020-03-01
影响因子：
5
通讯作者：
Kinoshita, Yoshikazu
中科院分区：
文献类型：
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作者：
Mishima, Yoshiyuki;Sonoyama, Hiroki;Kinoshita, Yoshikazu
以往的研究表明白细胞介素-33（IL-33）参与溃疡性结肠炎（UC）的发病机制，但具体机制尚不完全清楚。我们研究了IL-33介导的结肠稳态使用的机制的方法。IL 33（-/-）小鼠比野生型小鼠对硫酸葡聚糖钠诱导的急性结肠炎更耐受，并且在给予重组IL-33（rIL-33）后也显示出从结肠炎中恢复延迟。出乎意料的是，微阵列分析鉴定了rIL-33处理后小鼠结肠中Abcg 5/8基因的显著下调。ABCG 5/8是小肠和肝脏中已知的胆固醇转运蛋白，尽管其结肠活性尚未阐明，因此研究了其在IL-33介导的炎症中的作用。在体外，Toll样受体（TLR）刺激上调Caco 2和HCT-15细胞中ABCG 5/8 mRNA的表达，随后被rIL-33下调，而ABCG 5/8沿着其siRNA的抑制增加TLR刺激的IL-8的产生。总之，这些结果表明，结肠ABCG 5/8在TLR诱导的炎症中起调节作用，而人UC的组织学炎症与粘膜IL-33水平呈正相关，与结肠ABCG 5/8呈负相关。这是首次报道IL-33介导的结肠ABCG 5/8在结肠炎恢复期下调，表明它们参与UC发病机制并可能作为治疗靶点。发现IL-33通过在从结肠炎恢复期间下调保护性ABCG 5/8来维持粘膜炎症。这些结果可能有助于增加对IL-33介导的溃疡性结肠炎发病机制的理解，并可能有助于创造一种新的治疗策略。
Previous studies have suggested that interleukin-33 (IL-33) is involved in the pathogenesis of ulcerative colitis (UC), though the detailed mechanisms are not fully known. We investigated IL-33-mediated colonic homeostasis using a mechanistic method. Il33(-/-) mice were more tolerant to dextran sulfate sodium-induced acute colitis than the wild type and also showed delayed recovery from colitis with recombinant IL-33 (rIL-33) administration. Unexpectedly, microarray analysis identified significant downregulation of the Abcg5/8 genes in mouse colons following rIL-33 treatment. ABCG5/8 are known cholesterol transporters in the small intestine and liver, though their colon activities have not been elucidated, thus their role in IL-33-mediated inflammation was investigated. In vitro, toll-like receptor (TLR) stimulation upregulated ABCG5/8 mRNA expression in Caco2 and HCT-15 cells, with subsequent downregulation by rIL-33, while inhibition of ABCG5/8 along with their siRNA increased TLR-stimulated IL-8 production. Together, these results indicated that colonic ABCG5/8 play a regulatory role in TLR-induced inflammation, while histological inflammation in human UC was correlated positively with the level of mucosal IL-33 and inversely with that of colonic ABCG5/8. This is the first report of IL-33-mediated downregulation of colonic ABCG5/8 in a colitis recovery phase, indicating their involvement in UC pathogenesis and potential as a therapeutic target.The authors investigated the potential mechanisms of interleukin-33 (IL-33) in the pathogenesis of ulcerative colitis. IL-33 was found to sustain mucosal inflammation by down-regulation of protective ABCG5/8 during recovery from colitis. These results may help to increase understanding regarding the IL-33-mediated pathogenesis of ulcerative colitis and potentially contribute to creation of a novel therapeutic strategy.