Involvement of heat shock protein a4/apg-2 in refractory inflammatory bowel disease.
Involvement of heat shock protein a4/apg-2 in refractory inflammatory bowel disease.
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DOI：
10.1097/mib.0000000000000244
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发表时间：
2015-01
影响因子：
4.9
通讯作者：
Kudo M
中科院分区：
文献类型：
--
作者：
Adachi T;Sakurai T;Kashida H;Mine H;Hagiwara S;Matsui S;Yoshida K;Nishida N;Watanabe T;Itoh K;Fujita J;Kudo M
文章于2014年12月1日首次在线发布。补充数字内容在文本中可用。热休克蛋白A4（HSPA 4，也称为Apg-2）是热休克蛋白110家族的一员，其表达受多种形式的应激诱导。HSPA 4在肠道中的生理和病理功能仍有待阐明。我们通过产生HSPA 4缺陷小鼠并使用214例炎症性肠病（IBD）患者的人肠粘膜样本来评估HSPA 4的表达和功能。在IBD患者的结肠粘膜中，观察到HSPA 4的表达与抗凋亡蛋白Bcl-2、T细胞衍生的细胞因子IL-17或干细胞标记物如Sox 2之间存在显著相关性。在难治性溃疡性结肠炎（一种与癌症风险增加相关的疾病）中，结肠粘膜炎性细胞中HSPA 4和Bcl-2的表达增加。HSPA 4在人结直肠癌的癌细胞和免疫细胞中均过表达。HSPA 4或Bmi 1高表达的患者在随后的类固醇治疗后的反应率明显低于每个基因低表达的患者。HSPA 4缺陷小鼠在葡聚糖硫酸钠给药后表现出比对照小鼠更多的凋亡和炎性细胞中IL-17/IL-23的表达以及更少的Sox 2+细胞数量。将HspaA 4 +/−骨髓转导到野生型小鼠中降低了免疫应答。通过HSPA 4上调Bcl-2和IL-17，可控制肠道中的炎性细胞凋亡和免疫应答，这可能在IBD中产生治疗抗性。HSPA 4和Bmi 1将是一个有用的生物标志物难治性的临床过程和IBD患者的治疗策略的一个有前途的方法。
Article first published online 1 December 2014. Supplemental Digital Content is Available in the Text. Expression of heat shock protein A4 (HSPA4, also called Apg-2), a member of the HSP110 family, is induced by several forms of stress. The physiological and pathological functions of HSPA4 in the intestine remain to be elucidated. We assessed HSPA4 expression and function by generating HSPA4-deficient mice and using 214 human intestinal mucosa samples from patients with inflammatory bowel disease (IBD). In the colonic mucosa of patients with IBD, a significant correlation was observed between the expression of HSPA4 and antiapoptotic protein Bcl-2, a T-cell–derived cytokine IL-17 or stem cell markers, such as Sox2. In refractory ulcerative colitis, a condition associated with increased cancer risk, expression of HSPA4 and Bcl-2 was increased in inflammatory cells of colonic mucosae. HSPA4 was overexpressed both in cancer cells and immune cells of human colorectal cancers. Patients with high expression of HSPA4 or Bmi1 showed significantly lower response rates upon subsequent steroid therapy as compared with patients with low expression of each gene. HSPA4-deficient mice exhibit more apoptosis and less expression of IL-17/IL-23 in inflammatory cells and less number of Sox2+ cells after administration of dextran sodium sulfate than control mice. Transduction of HspaA4+/− bone marrow into wild-type mice reduced the immune response. Upregulation of Bcl-2 and IL-17 by HSPA4 would control apoptosis of inflammatory cells and immune response in the gut, which might develop treatment resistance in IBD. HSPA4 and Bmi1 would be a useful biomarker for refractory clinical course and a promising approach for a therapeutic strategy in patients with IBD.