From the Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany,; the Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
From the Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany,; the Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China.
J Biol Chem. 2013 Oct 18;288(42):30708-30719. doi: 10.1074/jbc.M113.478685. Epub 2013 Sep 4.
In fibrotic liver, connective tissue growth factor (CTGF) is constantly expressed in activated hepatic stellate cells (HSCs) and acts downstream of TGF-β to modulate extracellular matrix production. Distinct from other cell types in which Smad signaling plays major role in regulating CTGF production, TGF-β stimulated CTGF expression in activated HSCs is only in part dependent on Smad3. Other signaling molecules like MAPKs and PI3Ks may also participate in this process, and the underlying mechanisms have yet to be clarified. In this study, we report involvement of Stat3 activation in modulating CTGF production upon TGF-β challenge in activated HSCs. Stat3 is phosphorylated via JAK1 and acts as a critical ALK5 (activin receptor-like kinase 5) downstream signaling molecule to mediate CTGF expression. This process requires de novo gene transcription and is additionally modulated by MEK1/2, JNK, and PI3K pathways. Cell-specific knockdown of Smad3 partially decreases CTGF production, whereas it has no significant influence on Stat3 activation. The total CTGF production induced by TGF-β in activated HSCs is therefore, to a large extent, dependent on the balance and integration of the canonical Smad3 and Stat3 signaling pathways.
在纤维化的肝脏中，结缔组织生长因子（CTGF）在活化的肝星状细胞（HSCs）中持续表达，并作为 TGF-β 的下游因子调节细胞外基质的产生。与其他细胞类型不同，Smad 信号在调节 CTGF 产生中起主要作用，TGF-β 刺激活化的 HSCs 中 CTGF 的表达仅部分依赖于 Smad3。其他信号分子，如 MAPKs 和 PI3Ks，也可能参与这一过程，但其潜在机制尚未阐明。在这项研究中，我们报告了 Stat3 激活在 TGF-β 刺激活化的 HSCs 中调节 CTGF 产生中的作用。Stat3 通过 JAK1 磷酸化，作为 ALK5（激活素受体样激酶 5）下游信号分子发挥关键作用，介导 CTGF 的表达。这个过程需要新的基因转录，并受 MEK1/2、JNK 和 PI3K 途径的调节。Smad3 的细胞特异性敲低部分降低了 CTGF 的产生，而对 Stat3 的激活没有显著影响。因此，TGF-β 在活化的 HSCs 中诱导的总 CTGF 产生在很大程度上取决于经典的 Smad3 和 Stat3 信号通路之间的平衡和整合。
