Copper metabolism domain-containing 1 represses genes that promote inflammation and protects mice from colitis and colitis-associated cancer.
Copper metabolism domain-containing 1 represses genes that promote inflammation and protects mice from colitis and colitis-associated cancer.
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DOI：
10.1053/j.gastro.2014.04.007
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发表时间：
2014-07
期刊：
影响因子：
29.4
通讯作者：
Burstein E
中科院分区：
文献类型：
--
作者：
Li H;Chan L;Bartuzi P;Melton SD;Weber A;Ben-Shlomo S;Varol C;Raetz M;Mao X;Starokadomskyy P;van Sommeren S;Mokadem M;Schneider H;Weisberg R;Westra HJ;Esko T;Metspalu A;Kumar V;Faubion WA;Yarovinsky F;Hofker M;Wijmenga C;Kracht M;Franke L;Aguirre V;Weersma RK;Gluck N;van de Sluis B;Burstein E
转录因子NFκB的激活与炎症性肠病（IBD）的发生有关。COMMD 1是一种多种转运途径的调节因子，已被证明可限制NFκB的活化。我们研究了COMMD 1在小鼠结肠炎和人类IBD发病机制中的作用。我们建立了骨髓细胞中Commd 1特异性破坏的小鼠（Mye-K/O小鼠）;我们分析了免疫细胞群体和NFκB调控的基因的功能和表达。通过盲肠结扎和穿刺或腹腔内注射脂多糖（LPS）在Mye-K/O和野生型小鼠中诱导脓毒症，通过施用葡聚糖硫酸钠（DSS）诱导结肠炎，并且通过施用DSS和氧化偶氮甲烷诱导结肠炎相关的癌症。我们测量了29名IBD患者和16名非IBD患者（对照组）结肠活检组织中COMMD 1 mRNA的水平，并在一个独立的队列（17名IBD患者和22名对照组）中验证了结果。我们使用国际IBD遗传学联盟的数据搜索了COMMD 1中或附近与IBD相关的多态性，并进行了数量性状基因座分析。在比较Mye-K/O和野生型小鼠骨髓细胞之间的基因表达模式时，我们发现COMMD 1抑制LPS诱导的基因表达。Mye-K/O小鼠对LPS有更强烈的炎症反应，并发生更严重的败血症和结肠炎，死亡率更高。与野生型小鼠相比，患有结肠炎的Mye-K/O小鼠更多地发生结肠发育不良和肿瘤。我们在IBD患者的结肠活检组织和循环白细胞中观察到COMMD 1的表达减少。我们将COMMD 1附近的单核苷酸变异与该基因表达减少相关联，并将其与溃疡性结肠炎风险增加联系起来。骨髓细胞表达COMMD 1具有抗炎作用。COMMD 1的表达或功能降低可能参与IBD的发病机制。
Activation of the transcription factor NFκB has been associated with development of inflammatory bowel disease (IBD). COMMD1, a regulator of various transport pathways, has been shown to limit NFκB activation. We investigated the roles of COMMD1 in the pathogenesis of colitis in mice and IBD in humans. We created mice with specific disruption of Commd1 in myeloid cells (Mye-K/O mice); we analyzed immune cell populations and functions and expression of genes regulated by NFκB. Sepsis was induced in Mye-K/O and wild-type mice by cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide (LPS), colitis was induced by administration of dextran sodium sulfate (DSS), and colitis-associated cancer was induced by administration of DSS and azoxymethane. We measured levels of COMMD1 mRNA in colon biopsies from 29 patients with IBD and 16 patients without (controls), and validated findings in an independent cohort (17 patients with IBD and 22 controls). We searched for polymorphisms in or near COMMD1 that were associated with IBD using data from the International IBD Genetics Consortium and performed quantitative trait locus analysis. In comparing gene expression patterns between myeloid cells from Mye-K/O and wild-type mice, we found that COMMD1 represses expression of genes induced by LPS. Mye-K/O mice had more intense inflammatory responses to LPS and developed more severe sepsis and colitis, with greater mortality. More Mye-K/O mice with colitis developed colon dysplasia and tumors than wild-type mice. We observed reduced expression of COMMD1 in colon biopsies and circulating leukocytes from patients with IBD. We associated single nucleotide variants near COMMD1 with reduced expression of the gene and linked them with increased risk for ulcerative colitis. Expression of COMMD1 by myeloid cells has anti-inflammatory effects. Reduced expression or function of COMMD1 could be involved in the pathogenesis of IBD.
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影响因子：
30.8
作者：
通讯作者：
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影响因子：
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Kaikkonen, Minna U.;Spann, Nathanael J.;Heinz, Sven;Romanoski, Casey E.;Allison, Karmel A.;Stender, Joshua D.;Chun, Hyun B.;Tough, David F.;Prinjha, Rab K.;Benner, Christopher;Glass, Christopher K.
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Greten, Florian R.
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