Vascular endothelial growth factor promotes the activation of hepatic stellate cells in chronic schistosomiasis.
The activation of hepatic stellate cells (HSCs) is a key event in fibrotic pathogenesis. However, the mechanism involving activation of HSCs in chronic schistosomiasis is not entirely clear. Human HSC LX-2 and human umbilical vein endothelial cells (ECs) were cultured with Schistosoma japonicum antigens (SA) in vitro. Fibrosis-associated genes and cell proliferation were analyzed. HSCs were isolated from mice of chronic schistosomiasis with or without praziquantel (PZQ) treatment, followed by the microarray analysis for the liver fibrosis-associated pathways. Although SA inhibited the activation and proliferation of HSCs, it induced the EC proliferation and vascular endothelial growth factor-a (VEGF) production. VEGF significantly increased the proliferation of HSCs and upregulated the expression of collagen and α-smooth muscle actin. For in vivo study, we found that several fibrosis-associated pathways were involved in the HSCs during the reversal of liver fibrosis caused by schistosomiasis, including VEGF, platelet-derived growth factor, tumor necrosis factor and endothelin-1 pathways. The Ingenuity Pathway Analysis showed that VEGF directly regulated several pro-fibrotic and immune cytokine genes in HSCs, including integrin, fibronectin, interferon-γ, interleukin (IL)-6 and IL-10. Our data indicated the critical role of VEGF signaling in HSC activation in chronic schistosomiasis and highlighted several promising genes and pathways in HSCs as potential targets for therapeutic treatment of liver fibrosis.
Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China.|Comprehensive Laboratory, Ningbo International Travel Healthcare Center, Ningbo, China.
Jie
J
Luo
Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China.|Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX, USA.
Yuejin
Y
Liang
Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA.
Fanping
F
Kong
Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China.
Jingfan
J
Qiu
Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China.
Xinjian
X
Liu
Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China.
Ailing
A
Chen
Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA.
Bruce A
BA
Luxon
Center for International Health Research, Rhode Island Hospital, Providence, RI, USA.
Hannah W
HW
Wu
Department of Pathogen Biology, Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, China.
Yong
Y
Wang
D000199:Actins / Q000378:metabolism; D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology; D049109:Cell Proliferation; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005355:Fibrosis / Q000235:genetics; D055166:Hepatic Stellate Cells / Q000276:immunology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008099:Liver / Q000469:parasitology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D012549:Schistosoma japonicum / Q000276:immunology*; D012554:Schistosomiasis japonica / Q000188:drug therapy / Q000276:immunology*; D059467:Transcriptome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C541116:ACTA2 protein, human; D000199:Actins; D000947:Antigens, Helminth; D016207:Cytokines; D019332:Endothelin-1; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen