DMBT1 Is a Novel Gene Induced by IL-22 in Ulcerative Colitis
DMBT1 Is a Novel Gene Induced by IL-22 in Ulcerative Colitis
复制标题
DOI：
10.1002/ibd.21473
复制
发表时间：
2011-05-01
影响因子：
4.9
通讯作者：
Fujimori, Takahiro
中科院分区：
文献类型：
--
作者：
Fukui, Hirokazu;Sekikawa, Akira;Fujimori, Takahiro
背景：白细胞介素（IL）-22是近年来发现的一种细胞因子，在多种炎症性疾病中发挥重要作用。尽管IL-22受体1（IL-22 R1）在结肠上皮细胞中限制性表达，但IL-22在结肠疾病中的作用仍不清楚。在这项研究中，微阵列分析显示，在恶性脑肿瘤中删除1（DMBT 1）是一种新的上调基因在IL-22刺激的结肠癌细胞。因此，我们研究了DMBT 1和IL-22在溃疡性结肠炎（UC）组织中的作用，并探讨了IL-22刺激对DMBT 1表达的调控机制。方法：采用基因芯片技术研究IL-22刺激后SW 403细胞基因表达的变化。在SW 403细胞中，使用针对STAT 3的小干扰RNA（si）RNA或针对MEK、PI 3 K和核因子κ B（NF-κ B）的抑制剂，检测IL-22对DMBT 1表达的影响。通过启动子缺失和电泳迁移率变动分析（EMSA）确定负责IL-22诱导的DMBT 1启动子激活的元件。结果：IL-22处理后结肠癌细胞中DMBT 1的表达增强，其机制可能与STAT 3酪氨酸磷酸化和NF-κ B B活化有关。IL-22反应元件位于DMBT 1启动子区的-187和-179之间。UC黏膜中DMBT 1和IL-22 mRNA表达水平显著增强，且呈正相关，炎症上皮中IL-22阳性淋巴细胞数增加，IL-22 R1和DMBT 1表达增强。结论：IL-22/DMBT 1轴可能在UC的病理生理过程中起重要作用。（炎症性肠病2011;17：1177-1188）
Background: Interleukin (IL)-22 is a recently identified cytokine that is suggested to play pivotal roles in various inflammatory diseases. Although the IL-22 receptor 1 (IL-22R1) is restrictively expressed in epithelial cells in the colon, the role of IL-22 in colonic diseases still remains unclear. In this study microarray analyses revealed that deleted in malignant brain tumors 1 (DMBT1) is a novel upregulated gene in IL-22-stimulated colon cancer cells. Therefore, we investigated the involvement of DMBT1 and IL-22 in ulcerative colitis (UC) tissues and examined the mechanism regulating the expression of DMBT1 in response to IL-22 stimulation.Methods: Changes of gene expression in IL-22-stimulated SW403 cells were investigated by microarray analyses. The effects of IL-22 on DMBT1 expression were examined in SW403 cells using a small interfering RNA (si) RNA for STAT3 or inhibitors for MEK, PI3K, and nuclear factor kappa B (NF-kappa B). The element responsible for IL-22-induced DMBT1 promoter activation was determined by a promoter deletion and electrophoretic mobility shift assay (EMSA). Expression of IL-22, IL-22R1, and DMBT1 in UC tissues was analyzed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry.Results: IL-22 treatment enhanced the expression of DMBT1 through STAT3 tyrosine phosphorylation and NF-kappa B activation in colon cancer cells. The IL-22-responsive element was located between -187 and -179 in the DMBT1 promoter region. In the UC mucosa the levels of DMBT1 and IL-22 mRNA expression were significantly enhanced and positively correlated, the numbers of IL-22-positive lymphocytes were increased, and the expression of IL-22R1 and DMBT1 was enhanced in the inflamed epithelium.Conclusions: The IL-22/DMBT1 axis may play a pivotal role in the pathophysiology of UC. (Inflamm Bowel Dis 2011;17:1177-1188)