Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and the Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Biochem J. 2012 Oct 1;447(1):25-34. doi: 10.1042/BJ20112058.
Cholestatic liver injury may activate HSCs (hepatic stellate cells) to a profibrogenic phenotype, contributing to liver fibrogenesis. We have previously demonstrated the involvement of TLR (Toll-like receptor) 7 in the pathogenesis of biliary atresia. In the present study we investigated the ability of TLR7 to modulate the profibrogenic phenotype in HSCs. Obstructive jaundice was associated with significant down-regulation of TLR7. Primary HSCs isolated from BDL (bile duct ligation) rats with obstructive jaundice exhibited reduced expression of TLR7 and increased expression of α-SMA (α-smooth muscle actin) and collagen-α1 compared with sham rats, reflecting HSC-mediated changes. Treatment of primary activated rat HSCs and rat T6 cells with CL075, a TLR7 and TLR8 ligand, significantly decreased expression of MCP-1 (monocyte chemotactic protein-1), TGF-β1 (transforming growth factor-β1), collagen-α1 and MMP-2 (matrix metalloproteinase-2), and inhibited cell proliferation and migration. In contrast, silencing TLR7 expression with shRNA (short hairpin RNA) in T6 cells effectively blocked the effects of CL075 stimulation, reversing the changes in MCP-1, TGF-β1 and collagen-α1 expression and accelerating cell migration. Our results indicate that obstructive jaundice is associated with down-regulation of TLR7 and up-regulation of profibrogenic gene expression in HSCs. Selective activation of TLR7 may modulate the profibrogenic phenotype in activated HSCs associated with cholestatic liver injury.
胆汁淤积性肝损伤可能激活 HSCs（肝星状细胞）向致纤维化表型转化，促进肝纤维化的发生。我们之前已经证明 TLR（Toll 样受体）7 参与了胆道闭锁的发病机制。在本研究中，我们研究了 TLR7 调节 HSCs 致纤维化表型的能力。梗阻性黄疸与 TLR7 的显著下调有关。与假手术大鼠相比，从梗阻性黄疸 BDL（胆管结扎）大鼠分离的原代 HSCs 表现出 TLR7 表达降低，α-SMA（α-平滑肌肌动蛋白）和胶原-α1 表达增加，反映了 HSC 介导的变化。用 TLR7 和 TLR8 配体 CL075 处理原代激活的大鼠 HSCs 和大鼠 T6 细胞，显著降低 MCP-1（单核细胞趋化蛋白-1）、TGF-β1（转化生长因子-β1）、胶原-α1 和 MMP-2（基质金属蛋白酶-2）的表达，并抑制细胞增殖和迁移。相比之下，用 shRNA（短发夹 RNA）沉默 T6 细胞中的 TLR7 表达可有效阻断 CL075 刺激的作用，逆转 MCP-1、TGF-β1 和胶原-α1 表达的变化，并加速细胞迁移。我们的结果表明，梗阻性黄疸与 HSCs 中 TLR7 的下调和致纤维化基因表达的上调有关。TLR7 的选择性激活可能调节与胆汁淤积性肝损伤相关的激活 HSCs 的致纤维化表型。
