Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
Department of Laboratory Medicine, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan.
FASEB J. 2019 Nov;33(11):12554-12564. doi: 10.1096/fj.201900487R. Epub 2019 Aug 26.
() infection in lung causes pulmonary fibrosis, which leads to the irreversible reduction of pulmonary function. Fibrotic protein connective tissue growth factor (CTGF) expression has been confirmed to play a crucial role in lung fibrosis. However, the underlying signal pathway and effect of on CTGF expression in human lung fibroblasts are unclear. Our results revaled that caused time- and concentration-dependent increases in CTGF expression in human lung fibroblasts. A mechanistic investigation revealed that induced CTGF expression through TLR2 but not TLR4. The promoter activity assay indicated that -induced CTGF activity was mainly controlled by the promoter region at -747 to -184 bp, which contained signal transducer and activator of transcription 3 and activator protein 1 (AP-1) binding sites. Moreover, curcumin (AP-1 inhibitor) restrained -induced CTGF expression. also induced increases in AP-1 luciferase activity and DNA binding activity of c-Jun and c-Fos on the CTGF promoter. Furthermore, the knockdown of c-Jun by small interfering RNA attenuated -induced CTGF expression and AP-1 luciferase activity. A JNK inhibitor (SP600125) and a JNK dominant-negative mutant suppressed -induced CTGF expression. We also discovered that could induce the phosphorylation of JNK and c-Jun. Furthermore, SP600125 inhibited -induced c-Jun phosphorylation and AP-1- luciferase activity. -induced fibronectin expression was inhibited by anti-CTGF antibody. These results demonstrate that is activated through TLR2 to induce JNK activation, further increasing the DNA binding activity of c-Jun and c-Fos and finally inducing CTGF expression and extracellular matrix production.-Lee, H.-S., Hua, H.-S., Wang, C.-H., Yu, M.-C., Chen, B.-C., Lin, C.-H. induces connective tissue growth factor expression through the TLR2-JNK-AP-1 pathway in human lung fibroblasts.
() 感染肺部会导致肺纤维化，从而导致肺功能不可逆转地降低。已经证实纤维蛋白连接组织生长因子 (CTGF) 的表达在肺纤维化中起关键作用。然而， 对人肺成纤维细胞中 CTGF 表达的潜在信号通路和作用尚不清楚。我们的结果表明， 可引起人肺成纤维细胞中 CTGF 表达的时间和浓度依赖性增加。机制研究表明， 通过 TLR2 而不是 TLR4 诱导 CTGF 表达。启动子活性测定表明， - 诱导的 CTGF 活性主要受 -747 至 -184bp 的启动子区域控制，该区域包含信号转导和转录激活因子 3 和激活蛋白 1 (AP-1) 结合位点。此外，姜黄素 (AP-1 抑制剂) 抑制了 - 诱导的 CTGF 表达。 还诱导 CTGF 启动子上的 AP-1 荧光素酶活性和 c-Jun 和 c-Fos 的 DNA 结合活性增加。此外，小干扰 RNA 敲低 c-Jun 可减弱 - 诱导的 CTGF 表达和 AP-1 荧光素酶活性。JNK 抑制剂 (SP600125) 和 JNK 显性负突变体抑制了 - 诱导的 CTGF 表达。我们还发现， 可诱导 JNK 和 c-Jun 的磷酸化。此外，SP600125 抑制了 - 诱导的 c-Jun 磷酸化和 AP-1- 荧光素酶活性。抗 CTGF 抗体抑制了 - 诱导的纤维连接蛋白表达。这些结果表明， 通过 TLR2 激活， 诱导 JNK 激活，进一步增加 c-Jun 和 c-Fos 的 DNA 结合活性，最终诱导 CTGF 表达和细胞外基质产生。-李，H.-S.，华，H.-S.，王，C.-H.，于，M.-C.，陈，B.-C.，林，C.-H. 在人肺成纤维细胞中， 通过 TLR2-JNK-AP-1 通路诱导结缔组织生长因子表达。
