HBV promotes the proliferation of hepatic stellate cells via the PDGF-B/PDGFR-β signaling pathway in vitro

Bai,Qixuan; An,Jing; Wu,Xiaoning; You,Hong; Ma,Hong; Liu,Tianhui; Gao,Na; Jia,Jidong

doi:10.3892/ijmm.2012.1148

HBV promotes the proliferation of hepatic stellate cells via the PDGF-B/PDGFR-β signaling pathway in vitro

Authors:
- Qixuan Bai
- Jing An
- Xiaoning Wu
- Hong You
- Hong Ma
- Tianhui Liu
- Na Gao
- Jidong Jia
View Affiliations

Affiliations: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, P.R. China, Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, P.R. China
Published online on: October 4, 2012 https://doi.org/10.3892/ijmm.2012.1148
Pages: 1443-1450

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The activation of hepatic stellate cells (HSCs) is closely associated with liver fibrosis in chronic hepatitis B virus (HBV) infection. However, the molecular mechanisms leading to HSC activation remain unclear. It has been reported that the platelet-derived growth factor-B (PDGF-B)/PDGF receptor-β (PDGFR-β) signaling pathway is involved in this process. Thus, we investigated whether HBV and its protein contribute to HSC proliferation by the PDGF-B/PDGFR-β signaling pathway. HBV particles were purified from the supernatant of HepG2.2.15 cells by ultracentrifugation and the cell lines carrying HBV preS, e, c or x genes were obtained. After incubation with HBV particles or co-cultured with the cell lines expressed in the viral protein, the proliferation of LX-2 cells, an HSC cell line, were detected by flow cyto-metry and real-time PCR and the expression of molecules related to the PDGF-B/PDGFR-β signaling pathway were further measured. Our results indicated that HBV particles, c and x proteins promoted LX-2 proliferation and increased the mRNA levels of PDGF-B, PDGFR-β, collagen-I and α-smooth muscle actin (α-SMA), as well as the phosphorylation of PDGFR-β; however, the expression protein levels of PDGF-B and PDGFR-β remained unchanged. In conclusion, HBV particles and HBV c and x proteins promote HSC proliferation and fibrogenesis in vitro and the PDGF-B/PDGFR-β signaling pathway is important in this process.

View Figures

View References

1.	G Gutierrez-ReyesMC Gutierrez-RuizD KershenobichLiver fibrosis and chronic viral hepatitisArch Med Res38644651200710.1016/j.arcmed.2006.10.00117613356
2.	K BreitkopfC RoeyenI SawitzaL WickertJ FloegeAM GressnerExpression patterns of PDGF-A, -B, -C and -D and the PDGF-receptors alpha and beta in activated rat hepatic stellate cells (HSC)Cytokine31349357200510.1016/j.cyto.2005.06.00516039137
3.	M PinzaniS MilaniH HerbstExpression of platelet-derived growth factor and its receptors in normal human liver and during active hepatic fibrogenesisAm J Pathol14878580019968774134
4.	M PinzaniPDGF and signal transduction in hepatic stellate cellsFront Biosci7d1720d1726200210.2741/pinzani12133817
5.	F MarraM PinzaniR DeFrancoG LaffiP GentiliniInvolvement of phosphatidylinositol 3-kinase in the activation of extracellular signal-regulated kinase by PDGF in hepatic stellate cellsFEBS Lett376141145199510.1016/0014-5793(95)01261-07498528
6.	P CzochraB KlopcicE MeyerLiver fibrosis induced by hepatic overexpression of PDGF-B in transgenic miceJ Hepatol45419428200610.1016/j.jhep.2006.04.01016842882
7.	M PinzaniL GesualdoGM SabbahHE AbboudEffects of platelet-derived growth factor and other polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat-storing cellsJ Clin Invest8417861793198910.1172/JCI1143632592560
8.	F MarraGG ChoudhuryM PinzaniHE AbboudRegulation of platelet-derived growth factor secretion and gene expression in human liver fat-storing cellsGastroenterology1071110111719947926460
9.	K LehtiE AllenH Birkedal-HansenAn MT1-MMPPDGF receptor-beta axis regulates mural cell investment of the microvasculatureGenes Dev19979991200510.1101/gad.129460515805464
10.	P LindahlM HellstromM KalenParacrine PDGF-B/PDGF-Rbeta signaling controls mesangial cell development in kidney glomeruliDevelopment1253313332219989693135
11.	MA FeitelsonHM ReisNL TufanB SunJ PanZ LianPutative roles of hepatitis B x antigen in the pathogenesis of chronic liver diseaseCancer Lett2866979200910.1016/j.canlet.2008.12.01019201080
12.	GH GuoDM TanPA ZhuF LiuHepatitis B virus X protein promotes proliferation and upregulates TGF-beta1 and CTGF in human hepatic stellate cell line, LX-2Hepatobiliary Pancreat Dis Int85964200919208517
13.	S Martin-VilchezP Sanz-CamenoY Rodriguez-MunozThe hepatitis B virus X protein induces paracrine activation of human hepatic stellate cellsHepatology4718721883200810.1002/hep.2226518449922
14.	SM LouYM LiKM WangWM CaiHL WengExpression of platelet-derived growth factor-BB in liver tissues of patients with chronic hepatitis BWorld J Gastroenterol10385388200414760763
15.	WM CaiBB ZhangHL WengThe diagnostic value of eight serum indices for liver fibrosisZhonghua Gan Zang Bing Za Zhi122192222004(In Chinese).
16.	BB ZhangWM CaiHL WengDiagnostic value of platelet derived growth factor-BB, transforming growth factor-beta1, matrix metalloproteinase-1, and tissue inhibitor of matrix metalloproteinase-1 in serum and peripheral blood mononuclear cells for hepatic fibrosisWorld J Gastroenterol9249024962003
17.	M SeiferKH HeermannWH GerlichReplication of hepatitis B virus in transfected nonhepatic cellsVirology179300311199010.1016/0042-6822(90)90298-62219725
18.	XB PanJC HanY GaoL WeiHigh replicated hepatitis B virus induces apoptosis of hepatocytesZhonghua Yi Xue Za Zhi888408432008(In Chinese).
19.	N GaoW ChenQ ZhengCo-expression of Japanese encephalitis virus prM-E-NS1 antigen with granulocyte-macrophage colony-stimulating factor enhances humoral and anti-virus immunity after DNA vaccinationImmunol Lett1292331201010.1016/j.imlet.2009.12.023
20.	E HintermannM BayerJM PfeilschifterAD LusterU ChristenCXCL10 promotes liver fibrosis by prevention of NK cell mediated hepatic stellate cell inactivationJ Autoimmun35424435201010.1016/j.jaut.2010.09.00320932719
21.	J KitagawaT HaraH TsurumiCell cycle-dependent priming action of granulocyte colony-stimulating factor (G-CSF) enhances in vitro apoptosis induction by cytarabine and etoposide in leukemia cell linesJ Clin Exp Hematop5099105201010.3960/jslrt.50.99
22.	P Melgar-LesmesG CasalsM PautaApelin mediates the induction of profibrogenic genes in human hepatic stellate cellsEndocrinology15153065314201010.1210/en.2010-075420843995
23.	X LiuST ZhuH YouHepatitis B virus infects hepatic stellate cells and affects their proliferation and expression of collagen type IChin Med J (Engl)12214551461200919567171
24.	S ClementS PascarellaS ConzelmannC Gonelle-GispertK GuillouxF NegroThe hepatitis C virus core protein indirectly induces alpha-smooth muscle actin expression in hepatic stellate cells via interleukin-8J Hepatol52635643201010.1016/j.jhep.2009.10.03520347177
25.	M CoenenHD NischalkeB KramerHepatitis C virus core protein induces fibrogenic actions of hepatic stellate cells via toll-like receptor 2Lab Invest9113751382201110.1038/labinvest.2011.7821537327
26.	T GonzaloL BeljaarsM van de BovenkampLocal inhibition of liver fibrosis by specific delivery of a platelet-derived growth factor kinase inhibitor to hepatic stellate cellsJ Pharmacol Exp Ther321856865200710.1124/jpet.106.11449617369283
27.	S OgawaT OchiH ShimadaAnti-PDGF-B monoclonal antibody reduces liver fibrosis developmentHepatol Res4011281141201010.1111/j.1872-034X.2010.00718.x20880061
28.	E Borkham-KamphorstCR van RoeyenT OstendorfJ FloegeAM GressnerR WeiskirchenPro-fibrogenic potential of PDGF-D in liver fibrosisJ Hepatol4610641074200710.1016/j.jhep.2007.01.02917397961
29.	H IwamotoM NakamutaS TadaR SugimotoM EnjojiH NawataPlatelet-derived growth factor receptor tyrosine kinase inhibitor AG1295 attenuates rat hepatic stellate cell growthJ Lab Clin Med135406412200010.1067/mlc.2000.10597410811056
30.	HF SiX LvA GuoH JiangJ LiSuppressive effect of leflunomide on rat hepatic stellate cell proliferation involves on PDGF-BB-elicited activation of three mitogen-activated protein kinasesCytokine422431200810.1016/j.cyto.2008.01.01718343153
31.	N KinnmanC FrancozV BarbuThe myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesisLab Invest83163173200310.1097/01.LAB.0000054178.01162.E4