J Cell Commun Signal. 2010 Mar;4(1):15-23. doi: 10.1007/s12079-009-0083-1. Epub 2010 Feb 2.
Connective tissue growth factor (CTGF), also known as CCN2, is implicated in fibrosis through both extracellular matrix (ECM) induction and inhibition of ECM degradation. The role of CTGF in inflammation in cardiomyocytes is unknown. In some mesenchymal cell systems, CTGF mediates effects through TGF-beta or tyrosine kinase cell surface receptor, TrkA, signalling. In this study, cellular mechanisms by which CTGF regulates pathways involved in fibrosis and inflammation were explored. Murine H9c2 cardiomyocytes were treated with recombinant human (rh)CTGF and ECM formation gene expression: fibronectin, collagen type -I and -III and ECM degradation genes: TIMP-1, TIMP-2 and PAI-1 were found to be induced. CTGF treatment also increased pro-inflammatory cytokines TNF-alpha, IL-6, MCP-1 and IL-8. CTGF upregulated TGF-beta1 mRNA and rapidly induced phosphorylation of TrkA. The CTGF-induced pro-fibrotic and pro-inflammatory effects were blocked by anti-TGF-beta neutralizing antibody and Alk 5 inhibitor (SB431542). A specific blocker of TrkA activation, k252a, also abrogated CTGF-induced effects on fibrosis and gene expresison of MCP-1 and IL-8, but not TNF-alpha or IL-6. Collectively, this data implicates CTGF in effects on pro-fibrotic genes and pro-inflammatory genes via TGF-beta pathway signalling and partly through TrkA.
结缔组织生长因子（CTGF），也称为 CCN2，通过细胞外基质（ECM）诱导和抑制 ECM 降解，在纤维化中起作用。CTGF 在心肌细胞炎症中的作用尚不清楚。在一些间质细胞系统中，CTGF 通过 TGF-β或酪氨酸激酶细胞表面受体 TrkA 信号转导来介导作用。在这项研究中，探讨了 CTGF 调节纤维化和炎症相关途径的细胞机制。用重组人（rh）CTGF 处理鼠 H9c2 心肌细胞，发现 ECM 形成基因表达：纤连蛋白、胶原 I 型和 III 型，以及 ECM 降解基因：TIMP-1、TIMP-2 和 PAI-1 均被诱导。CTGF 处理还增加了促炎细胞因子 TNF-α、IL-6、MCP-1 和 IL-8。CTGF 上调 TGF-β1 mRNA 并迅速诱导 TrkA 磷酸化。抗 TGF-β中和抗体和 Alk 5 抑制剂（SB431542）阻断了 CTGF 诱导的促纤维化和促炎作用。TrkA 激活的特异性阻断剂 k252a 也消除了 CTGF 对纤维化和 MCP-1 和 IL-8 基因表达的影响，但对 TNF-α或 IL-6 没有影响。总之，这些数据表明 CTGF 通过 TGF-β途径信号转导和部分通过 TrkA 对促纤维化基因和促炎基因有影响。
