Tumor necrosis factor-alpha induces VCAM-1-mediated inflammation via c-Src-dependent transactivation of EGF receptors in human cardiac fibroblasts.
Tumor necrosis factor-alpha induces VCAM-1-mediated inflammation via c-Src-dependent transactivation of EGF receptors in human cardiac fibroblasts.
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DOI：
10.1186/s12929-015-0165-8
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发表时间：
2015-07-15
影响因子：
11
通讯作者：
Yang CM
中科院分区：
文献类型：
--
作者：
Lin CC;Pan CS;Wang CY;Liu SW;Hsiao LD;Yang CM
肿瘤坏死因子-α (TNF-α)是一种促炎细胞因子，在组织损伤和炎症性疾病区域升高。TNF-α对成纤维细胞的有害作用可能通过上调血管细胞粘附分子-1 （VCAM-1）等粘附分子介导的心脏炎症加重。然而，TNF-α-诱导心肌成纤维细胞中VCAM-1表达的机制尚不清楚。本研究旨在探讨TNF-α在VCAM-1表达中的作用及其对人心脏成纤维细胞（hcf）的影响。本研究采用原代培养HCFs。Western blotting、real - time-quantitative PCR及启动子活性分析结果表明，TNF-α-诱导的VCAM-1表达是通过TNF受体（TNFR） 1依赖性基因上调介导的。TNF-α转激活c- src依赖性EGF受体（EGFR）激活TNFR1，连接PI3K/Akt级联，然后导致NF-κB的转录活性。此外，启动子报告子实验结果表明，磷酸化的p65 NF-κB开启了VCAM-1基因的表达。随后，VCAM-1的上调促进了单核细胞对TNF-α刺激的hcf的粘附。综上所述，这些结果表明，在hcf中，通过c- src介导的EGFR/PI3K/Akt级联反应激活NF-κB是TNF-α-诱导的VCAM-1表达所必需的。最后，增加的VCAM-1增强了单核细胞粘附在TNF-α激发的hcf上。了解TNF-α上调VCAM-1对hcf的作用机制，可为心脏损伤或炎症性疾病的合理治疗干预提供依据。
Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine and elevated in the regions of tissue injury and inflammatory diseases. The deleterious effects of TNF-α on fibroblasts may aggravate heart inflammation mediated through the up-regulation of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1). However, the mechanisms underlying TNF-α-induced VCAM-1 expression in cardiac fibroblasts remain unknown. This study aimed to investigate the roles of TNF-α in VCAM-1 expression and its effects on human cardiac fibroblasts (HCFs). The primary culture HCFs were used in this study. The results obtained with Western blotting, real time-quantitative PCR, and promoter activity analyses showed that TNF-α-induced VCAM-1 expression was mediated through TNF receptor (TNFR) 1-dependent gene up-regulation. Activation of TNFR1 by TNF-α transactivated c-Src-dependent EGF receptor (EGFR) linking to PI3K/Akt cascade, and then led to transcriptional activity of NF-κB. Moreover, the results of promoter reporter assay demonstrated that the phosphorylated p65 NF-κB turned on VCAM-1 gene expression. Subsequently, up-regulation of VCAM-1 promoted monocytes adhesion to HCFs challenged with TNF-α determined by cell adhesion assay. Taken together, these results indicate that in HCFs, activation of NF-κB by c-Src-mediated transactivation of EGFR/PI3K/Akt cascade is required for TNF-α-induced VCAM-1 expression. Finally, increased VCAM-1 enhances monocytes adhering to HCFs challenged with TNF-α. Understanding the mechanisms of VCAM-1 up-regulated by TNF-α on HCFs may provide rationally therapeutic interventions for heart injury or inflammatory diseases.