Inhibitory effect of emodin on tissue inhibitor of metalloproteinases-1 (TIMP-1) expression in rat hepatic stellate cells.
Emodin inhibited expression of both transforming growth factor beta1 (TGFbeta1)- and phorbol ester (PMA)-induced tissue inhibitors of metalloproteinase-1 (TIMP-1) in an immortalized rat hepatic stellate cell line, HSC-T6, by Western blot and reverse transcription polymerase chain reaction. Reporter gene assays showed that emodin reduced both basal and PMA-induced activated protein-1 (AP-1) promoter activities. Electrophoretic mobility shift assay revealed that emodin reduced AP-1 DNA binding activities in HSC-T6 cells. AP-1 components analysis showed that emodin also attenuated JunD mRNA expression. Furthermore, emodin markedly inhibited TGFbeta1-induced p42/p44 mitogen-activated protein kinase phosphorylation but did not alter PMA induction. We conclude that emodin effectively inhibits PMA- and TGFbeta1-stimulated TIMP-1 expression in hepatic stellate cells by suppressing the AP-1 signaling pathway and extracellular signal-regulated kinase activation, respectively. These data provide new insight into the cellular and molecular mechanisms of emodin against liver fibrosis.
Gui
Min
M
Department of Pharmacology, School of Pharmacy, Second Military Medical University, Guo He Road 325, Shanghai 200433, PR China.
Zhang
Yue Fan
YF
Xiao
Zhen Yu
ZY
Sun
Peng
P
Dai
Jian Feng
JF
Wang
Shuo Feng
SF
Rui
Yao Cheng
YC
Zhang
Jun Ping
JP
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D004642:Emodin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology*; D051379:Mice; D010766:Phosphorylation; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism
D004791:Enzyme Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D048049:Extracellular Signal-Regulated MAP Kinases; D004642:Emodin