XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease

被引:1202
作者
Kaser, Arthur [2 ]
Lee, Ann-Hwee [1 ]
Franke, Andre [4 ]
Glickman, Jonathan N. [3 ]
Zeissig, Sebastian [2 ]
Tilg, Herbert [5 ,6 ]
Nieuwenhuis, Edward E. S. [7 ]
Higgins, Darren E. [8 ]
Schreiber, Stefan [4 ,9 ]
Glimcher, Laurie H. [1 ]
Blumberg, Richard S. [2 ]
机构
[1] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA
[2] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gastroenterol,Dept Med, Boston, MA 02115 USA
[3] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA
[4] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany
[5] Innsbruck Med Univ, Dept Med, Christian Doppler Res Lab Gut Inflammat, A-6020 Innsbruck, Austria
[6] Innsbruck Med Univ, Dept Med, Div Gastroenterol & Hepatol, A-6020 Innsbruck, Austria
[7] Erasmus MC Sophia Childrens Hosp, Div Pediat Gastroenterol, NL-3000 GE Rotterdam, Netherlands
[8] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA
[9] Univ Hosp Schleswig Holstein, Dept Med 1, D-24105 Kiel, Germany
基金
奥地利科学基金会;
关键词
D O I
10.1016/j.cell.2008.07.021
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 hypothesized that a stressful environmental milieu in a rapidly proliferating tissue might instigate a proinflammatory response. We report that Xbp1 deletion in intestinal epithelial cells (IECs) results in spontaneous enteritis and increased susceptibility to induced colitis secondary to both Paneth cell dysfunction and an epithelium that is overly reactive to inducers of IBD such as bacterial products (flagellin) and TNF alpha. An association of XBP1 variants with both forms of human IBD (Crohn's disease and ulcerative colitis) was identified and replicated (rs35873774; p value 1.6 x 10(-5)) with novel, private hypomorphic variants identified as susceptibility factors. Hence, intestinal inflammation can originate solely from XBP1 abnormalities in IECs, thus linking cell-specific ER stress to the induction of organ-specific inflammation.
引用
收藏
页码:743 / 756
页数:14
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