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2015 ; 5
(ä): 16552
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Activation of TGF-?1-CD147 positive feedback loop in hepatic stellate cells
promotes liver fibrosis
#MMPMID26559755
Li HY
; Ju D
; Zhang DW
; Li H
; Kong LM
; Guo Y
; Li C
; Wang XL
; Chen ZN
; Bian H
Sci Rep
2015[Nov]; 5
(ä): 16552
PMID26559755
show ga
Activation of hepatic stellate cells (HSCs) by transforming growth factor-?1
(TGF-?1) initiates HBV-associated fibrogenesis. The mechanism of TGF-?1
modulating HSC activation is not fully uncovered. We hypothesized a positive
feedback signaling loop of TGF-?1-CD147 promoting liver fibrogenesis by
activation of HSCs. Human HSC cell line LX-2 and spontaneous liver fibrosis model
derived from HBV transgenic mice were used to evaluate the activation of
molecules in the signaling loop. Wound healing and cell contraction assay were
performed to detect the CD147-overexpressed HSC migration and contraction. The
transcriptional regulation of CD147 by TGF-?1/Smad4 was determined using
dual-luciferase reporter assay and chromatin immunoprecipitation. We found that a
positive reciprocal regulation between TGF-?1 and CD147 mediated HSC activation.
CD147 over-expression promoted HSC migration and accelerated TGF-?1-induced cell
contraction. Phosphorylation of Smad2 and Smad3 in cooperation with Smad4
mediated the TGF-?1-regulated CD147 expression. Smad4 activated the transcription
by direct interaction with CD147 promoter. Meanwhile, CD147 modulated the
activated phenotype of HSCs through the ERK1/2 and Sp1 which up-regulated ?-SMA,
collagen I, and TGF-?1 synthesis. These findings indicate that TGF-?1-CD147 loop
plays a key role in regulating the HSC activation and combination of TGF-?
receptor inhibitor and anti-CD147 antibody might be promised to reverse
fibrogenesis.