title: Selective activation of Toll-like receptor 7 in activated hepatic stellate cells may modulate their profibrogenic phenotype.
abstract: 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.
authors: 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.
authors: Ming-Huei
authors: MH
authors: Chou
authors: Ying-Hsien
authors: YH
authors: Huang
authors: Tsun-Mei
authors: TM
authors: Lin
authors: Yung-Ying
authors: YY
authors: Du
authors: Po-Chin
authors: PC
authors: Tsai
authors: Chih-Sung
authors: CS
authors: Hsieh
authors: Jiin-Haur
authors: JH
authors: Chuang
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D041781:Jaundice, Obstructive / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010641:Phenotype; D011804:Quinolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D024042:Collagen Type I; D011804:Quinolines; D034741:RNA, Small Interfering; D013844:Thiazoles; D051199:Toll-Like Receptor 7; C551788:CL 075; C489639:TLR7 protein, rat; C498862:Acta2 protein, rat