TNF-α stimulates colonic myofibroblast migration via COX-2 and Hsp27.
TNF-α stimulates colonic myofibroblast migration via COX-2 and Hsp27.
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TNF-α 通过 COX-2 和 Hsp27 刺激结肠肌成纤维细胞迁移。
DOI：
10.1016/j.jss.2016.04.034
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Yoo,James
中科院分区：
文献类型：
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作者：
Saini,Shyla;Liu,Tiegang;Yoo,James
背景：克罗恩病（CD）是一种以纤维化狭窄为特征的慢性炎症性肠病。肌成纤维细胞（MFBs）是胃肠道的基质细胞，在乳糜泻患者中数量增加，是参与病理性纤维化的关键效应细胞。MFB是肿瘤坏死因子α (TNF-α)的已知靶标，TNF-α是一种促炎细胞因子，与CD的病理生理密切相关。然而，TNF-α促进纤维化的确切机制仍不完全清楚。在这里，我们首次证明TNF-α通过环氧化酶2 （COX-2）和热休克蛋白27 （Hsp27）途径增加MFB迁移。材料与方法将人结肠MFB细胞株18Co培养于35 × 10 mm的细胞培养皿中，从8 ~ 14代开始使用。在存在或不存在几种抑制剂（NS398, SB203580, Hsp27 siRNA）的情况下，Anin体外刮擦法评估TNF-α (10 ng/mL)对MFB迁移24小时的影响。结果stnf -α显著增加MFB在24 h内的迁移，TNF-α也导致COX-2表达增加，并刺激Hsp27在丝氨酸82处的快速磷酸化。P38 MAPK抑制剂SB203580对TNF-α-诱导的COX-2表达、Hsp27磷酸化和MFB迁移均有显著抑制作用（P< 0.05）。COX-2的直接抑制剂NS398 （P< 0.05）和靶向Hsp27的siRNA也能显著抑制TNF-α-诱导的MFB迁移（P< 0.05）。结论stnf -α通过P38 mapk介导的COX-2和Hsp27活化促进结肠MFB迁移。进一步阐明这些炎症信号通路可能会为治疗cd相关的纤维化和狭窄提供新的治疗靶点。
BackroundCrohn's disease (CD) is a chronic inflammatory enteropathy characterized by fibrotic strictures. Myofibroblasts (MFBs) are stromal cells of the gastrointestinal tract found in increased numbers in patients with CD and represent the key effector cells involved in pathologic fibrosis. MFB is a known target of tumor necrosis factor alpha (TNF-α), a proinflammatory cytokine strongly implicated in the pathophysiology of CD. However, the precise mechanisms through which TNF-α contributes to fibrosis remain incompletely understood. Here, we demonstrate for the first time that TNF-α increases MFB migration through the cyclooxygenase 2 (COX-2) and heat-shock protein 27 (Hsp27) pathways.Materials and methodsThe human colonic MFB cell line 18Co was grown to confluence on 35 × 10 mm cell culture dishes and used from passages 8-14. Anin vitroscratch assay assessed the effect of TNF-α (10 ng/mL) on MFB migration over 24 h in the presence or absence of several inhibitors (NS398, SB203580, Hsp27 siRNA).ResultsTNF-α significantly increased MFB migration over 24 h. TNF-α also led to the increased expression of COX-2 and stimulated rapid phosphorylation of Hsp27 at serine 82. TNF-α-induced COX-2 expression, Hsp27 phosphorylation, and MFB migration were all significantly inhibited by the P38 MAPK inhibitor SB203580 (P< 0.05). TNF-α-induced MFB migration was also significantly inhibited by NS398 (P< 0.05), a direct inhibitor of COX-2, and by siRNA targeting Hsp27 (P< 0.05).ConclusionsTNF-α stimulates colonic MFB migration through P38 MAPK-mediated activation of COX-2 and Hsp27. Further elucidating these inflammatory signaling pathways may lead to novel therapeutic targets for the treatment of CD-related fibrosis and strictures.