Effects of retinoic acid on proliferation, phenotype and expression of cyclin-dependent kinase inhibitors in TGF-&beta;1-stimulated rat hepatic stellate cells

doi:10.3748/wjg.v6.i6.819

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Gastroenterol. Dec 15, 2000; 6(6): 819-823
Published online Dec 15, 2000. doi: 10.3748/wjg.v6.i6.819

Effects of retinoic acid on proliferation, phenotype and expression of cyclin-dependent kinase inhibitors in TGF-β1-stimulated rat hepatic stellate cells

Guang Cun Huang, Jin Sheng Zhang, Yue E Zhang

Guang Cun Huang, Jin Sheng Zhang, Yue E, Zhang Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China

Guang Cun Huang, graduated from Medical Center of Fudan University (former Shanghai Medical University) in 1996, majoring in forensic medicine, now assistant and master at the Department of Pathology, School of Basic Medical Sciences, Fudan University, specialized in the study of hepatic pathology, having 3 papers published.

Author contributions: All authors contributed equally to the work.

Supported by the National Natural Science Foundation of China, No.3967 0287 and by the Scientific Research Foundation for Doctorate Education, State Education Commission, No. 96026530

Correspondence to: Dr. Guang Cun Huang, Department of Pathology, Medical Center of Fudan University (former Shanghai Medical University), 138 Yixueyuan Road, Shanghai 200032, China. Email: zdxu@shmu.edu.cn

Telephone: 0086-21-64041900 Ext.2537

Received: July 17, 2000
Revised: September 12, 2000
Accepted: September 19, 2000
Published online: December 15, 2000

Abstract

AIM: To study the molecular mechanisms of retinoic acid (RA) on proliferation and expression of cyclin-dependent kinase inhibitors (CKI), i.e. p16, p21 and p27 in cultured rat hepatic stellate cells (HSC) stimulated with transforming growth factor beta 1 (TGF-β1).

METHODS: HSC were isolated from healthy rat livers and cultured. After stimulated with 1 mg/L TGF-β1, subcultured HSC were treated with or without 1 nmol/L RA. MTT assay, immunocytochemistry (ICC) for p16, p21, p27 and α-smooth muscle actin (α -SMA) protein, in situ hybridization (ISH) for retinoic acid receptor beta 2 (RAR-β2) and p16, p21 and p27 mRNA and quantitative image analysis (partially) were performed.

RESULTS: RA inhibited HSC proliferation (41.50%, P < 0.05), decreased the protein level of α-SMA (55.09%, P < 0.05), and induced HSC to express RAR-β2 mRNA. In addition, RA increased the protein level of p16 (218.75%, P < 0.05) and induced p21 protein expression; meanwhile, p27 was undetectable by ICC in both control and RA-treated HSC. However, RA had no influence on the mRNA levels of p16, p21 or p27 as determined by ISH.

CONCLUSION: Up-regulation of p16 and p21 on post-transcriptional level may contribute, in part, to RA inhibition of TGF-β1 initiated rat HSC activation in vitro.

Keywords: retinoic acid; cyclin-dependent kinase inhibitor; hepatic stellate cell; cell culture; transforming growth factor beta 1; liver fibrosis