Herb medicine Inchin-ko-to (TJ-135) regulates PDGF-BB-dependent signaling pathways of hepatic stellate cells in primary culture and attenuates development of liver fibrosis induced by thioacetamide administration in rats.
OBJECTIVE
We studied the effect of Inchin-ko-to (TJ-135), a herb medicine that has been clinically used for liver cirrhosis in Japan, on liver fibrosis in a rat model and on the function of stellate cells.


METHODS
Rat liver fibrosis was generated by thioacetamide (TAA) administration. DNA synthesis was assessed by 5-bromo-2'-deoxyuridine incorporation assay. Protein expression was analysed by western blotting. Collagen and fibronectin mRNA expression were analysed by reverse transcription-polymerase chain reaction (RT-PCR).


RESULTS
TJ-135 improved liver fibrosis induced in rats by TAA administration. TJ-135 reduced collagen deposition and the expression of smooth muscle alpha-actin in fibrotic liver tissues and decreased the serum level of hyaluronic acid. In primary-cultured stellate cells, TJ-135 suppressed DNA synthesis and the expression of collagen alpha 1(I), collagen III, and fibronectin mRNAs. It hampered DNA synthesis and migration of PDGF-BB-stimulated stellate cells through inhibiting phosphorylation of PDGF receptor-beta and down-stream signaling pathways. Among TJ-135 components, 3-methyl-1,6,8-trihydroxyanthraquinone (emodin) derived from Rhei rhizoma was found to be the most active molecule.


CONCLUSIONS
TJ-135 and emodin regulate PDGF-dependent events in stellate cells and attenuate the development of liver fibrosis. Their clinical use may be beneficial for the therapy of human liver fibrosis.
Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan.
Yukihiro
Y
Imanishi
Naoto
N
Maeda
Kohji
K
Otogawa
Shuichi
S
Seki
Hiroko
H
Matsui
Norifumi
N
Kawada
Tetsuo
T
Arakawa
D000199:Actins / Q000378:metabolism; D000818:Animals; D000077214:Becaplermin; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D004642:Emodin / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017208:Rats, Wistar; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013853:Thioacetamide
D000199:Actins; D004365:Drugs, Chinese Herbal; D016326:Extracellular Matrix Proteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C078038:inchinko-to; D013853:Thioacetamide; D000077214:Becaplermin; D004247:DNA; D020797:Receptor, Platelet-Derived Growth Factor beta; D004642:Emodin