XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease.
XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease.
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DOI：
10.1016/j.cell.2008.07.021
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发表时间：
2008-09-05
期刊：
影响因子：
64.5
通讯作者：
Blumberg RS
中科院分区：
文献类型：
--
作者：
Kaser A;Lee AH;Franke A;Glickman JN;Zeissig S;Tilg H;Nieuwenhuis EE;Higgins DE;Schreiber S;Glimcher LH;Blumberg RS
炎症性肠病(IBD)是由于肠道微生物区系的粘膜免疫异常所致。转录因子XBP1是内质网(ER)应激反应的关键组成部分，是分泌细胞发育和维持所必需的，并与JNK激活有关。我们报道了肠上皮细胞中XBP1基因的缺失导致自发性肠炎和继发性结肠炎的易感性增加，这是由于潘氏细胞缺陷和肠上皮细胞对IBD诱导剂、肿瘤坏死因子α和鞭毛蛋白的过度反应所致。XBP1变异与人类炎症性肠病相关(rs35873774，P值1.6×10−5)被鉴定为易感因素，并与新的、私人亚型变异进行复制。因此，肠道炎症可以完全源于IEC中XBP1的异常，从而将细胞特异性内质网应激与器官特异性炎症的诱导联系起来。我们报道了第一个由人类IBD遗传危险因素的改变引起的自发性肠炎的小鼠模型。
Inflammatory bowel disease (IBD) has been attributed to aberrant mucosal immunity to the intestinal microbiota. The transcription factor XBP1, a key component of the endoplasmic reticulum (ER) stress response, is required for development and maintenance of secretory cells and linked to JNK activation. We report that XBP1 deletion in intestinal epithelial cells (IEC) results in spontaneous enteritis and increased susceptibility to induced colitis secondary to both Paneth cell deficiency and overactive responses of the intestinal epithelial cell (IEC) to the IBD-inducers, TNFα and flagellin. An association of XBP1 variants with human IBD was identified and replicated (rs35873774, P-value 1.6×10−5) with novel, private hypomorphic variants identified as susceptibility factors. Hence, intestinal inflammation can originate solely from XBP1 abnormalities in IEC thus linking cell-specific ER stress to the induction of organ-specific inflammation. We report the first mouse model of spontaneous intestinal inflammation arising from alterations in a genetic risk factor for human IBD.
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