Importance of inhibitor of DNA binding/differentiation 2 in hepatic stellate cell differentiation and proliferation.
OBJECTIVE
In liver fibrosis, activated hepatic stellate cells (HSC) are transformed into myofibroblasts. Helix-loop-helix (HLH) transcriptional factors such as MyoD regulate the differentiation of myocytes, and the inhibitor of DNA binding/differentiation (Id) family comprises dominant negative HLH transcriptional regulators that inhibit differentiation and promote cell proliferation. In the present study, we investigated how the Id family proteins regulate HSC.


METHODS
In primary rat HSC, inhibitor of DNA binding/differentiation (Id)2 and alpha-smooth muscle actin (alpha-SMA) mRNA expression increased 4 days after isolation. Next we established Id2 expressing HSC (HSC-T6-Id2-green fluorescent protein (GFP)) using HSC-T6 cells with retrovirus that expressed GFP-tagged Id2.


RESULTS
HSC-T6-Id2-GFP increased cell proliferation with cyclin D1 expression. In contrast, alpha-SMA expression wassuppressed. Real-time reverse transcription-polymerase chain reaction analysis showed Id2 induction significantly suppressed alpha-SMA, collagen-1, matrix metalloproteinase (MMP)-2, and MMP-9 mRNA (P < 0.05) but had no effect on tissue inhibitor of metalloproteinase or transforming growth factor-beta1 levels.


CONCLUSIONS
These findings suggest Id2, an HLH transcriptional regulator, plays an important regulatory role in the proliferation and differentiation of HSC.
Tajima
Kunihiko
K
Department of Molecular Science and Applied Medicine (Gastroenterology and Hepatology), Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
Terai
Shuji
S
Takami
Taro
T
Kawaguchi
Kotaro
K
Okita
Kiwamu
K
Sakaida
Isao
I