Involvement of interleukin-17A-induced expression of heat shock protein 47 in intestinal fibrosis in Crohn's disease
Involvement of interleukin-17A-induced expression of heat shock protein 47 in intestinal fibrosis in Crohn's disease
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DOI：
10.1136/gutjnl-2013-305632
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发表时间：
2014-12-01
期刊：
影响因子：
24.5
通讯作者：
Chiba, Tsutomu
中科院分区：
文献类型：
--
作者：
Honzawa, Yusuke;Nakase, Hiroshi;Chiba, Tsutomu
目的肠纤维化是克罗恩病(CD)的重要临床问题。热休克蛋白(HSP)47是一种胶原特异性分子伴侣，参与纤维化疾病。然而，热休克蛋白47诱导与镉有关的肠纤维化的分子机制仍不清楚。本研究旨在探讨白细胞介素17A(IL-17A)诱导的热休克蛋白47(HSP47)在CD型肠纤维化中的作用。检测IBD患者肠组织中HSP47和IL-17A的设计表达。检测IBD患者肠道上皮下肌成纤维细胞(ISEMF)和经IL-17A处理的CCD18Co细胞中HSP47和I型胶原的表达。我们通过给HSP47注射短发夹状RNA(ShRNA)来检测HSP47在IL-17A诱导的I型胶原表达中的作用，并使用特异性的抑制剂在CD-18Co细胞中研究了IL-17A诱导的HSP47表达的信号通路。免疫组织化学显示HSP47表达于α-平滑肌肌动蛋白(α-SMA)阳性细胞，活动期CD患者肠组织中HSP47阳性细胞数明显增加。IL-17A增强ISEMF和CD-18Co细胞中HSP47和I型胶原的表达。抑制IL-17A诱导的I型胶原表达，IL-17A信号通路分析显示c-jun氨基末端激酶参与了IL-17A诱导的HSP47表达。结论IL-17A诱导的HSP47表达参与了I型胶原的表达，可能参与了CD的肠纤维化。
Objective Intestinal fibrosis is a clinically important issue in Crohn's disease (CD). Heat shock protein (HSP) 47 is a collagen-specific molecular chaperone involved in fibrotic diseases. The molecular mechanisms of HSP47 induction in intestinal fibrosis related to CD, however, remain unclear. Here we investigated the role of interleukin (IL)-17A-induced HSP47 expression in intestinal fibrosis in CD.Design Expressions of HSP47 and IL-17A in the intestinal tissues of patients with IBD were determined. HSP47 and collagen I expressions were assessed in intestinal subepithelial myofibroblasts (ISEMFs) isolated from patients with IBD and CCD-18Co cells treated with IL-17A. We examined the role of HSP47 in IL-17A-induced collagen I expression by administration of short hairpin RNA (shRNA) to HSP47 and investigated signalling pathways of IL-17A-induced HSP47 expression using specific inhibitors in CCD-18Co cells.Results Gene expressions of HSP47 and IL-17A were significantly elevated in the intestinal tissues of patients with active CD. Immunohistochemistry revealed HSP47 was expressed in alpha-smooth muscle actin (alpha-SMA)-positive cells and the number of HSP47-positive cells was significantly increased in the intestinal tissues of patients with active CD. IL-17A enhanced HSP47 and collagen I expressions in ISEMFs and CCD-18Co cells. Knockdown of HSP47 in these cells resulted in the inhibition of IL-17A-induced collagen I expression, and analysis of IL-17A signalling pathways revealed the involvement of c-Jun N-terminal kinase in IL-17A-induced HSP47 expression.Conclusions IL-17A-induced HSP47 expression is involved in collagen I expression in ISEMFs, which might contribute to intestinal fibrosis in CD.