Hepatocyte growth factor in dampening liver immune-mediated pathology in acute viral hepatitis without compromising antiviral activity.
OBJECTIVE
Hepatocyte growth factor (HGF) is a pleiotropic cytokine related with cell proliferation and survival; however, its role in viral hepatitis is not elucidated. In this study, we studied HGF immune role in viral hepatitis.


METHODS
Mice received hydrodynamically delivered HGF plasmid or control plasmid and then infected with adenovirus, and parameters of immune-mediated liver damage were evaluated. We studied dendritic cell (DC) activation in the presence of HGF. T cells collected from infected mice were restimulated with virally infected DC to measure cytokine production in vitro.


RESULTS
HGF ameliorated the liver inflammation during viral hepatitis as alanine transferase, intrahepatic lymphocytes, and splenocyte counts were diminished by HGF. Lower histological scores of liver pathology were observed in the HGF group. DC from the HGF group expressed reduced CD40. The hepatic expression and serum concentration of IL-12p40 were diminished in HGF-transfected mice. In vitro experiments with DC confirmed that HGF diminished CD40 expression and IL-12p40 production. The expression and serum levels of IFN-γ, IL-6 and CXCL9 were significantly decreased in the HGF group. HGF overexpression diminished the expression and concentration of IL-10 and TGF-β. The frequency of PD-1(+) Tim-3(+) in CD8 T cells was decreased by HGF overexpression. Moreover, T cells in the HGF group at day 14 secreted more IFN-γ and TNF-α than those in the control group when restimulated with virally infected DC.


CONCLUSIONS
HGF modulated DC activation and T cell priming, thereby limiting the immune-mediated damage in the liver. However, viral clearance was not compromised by HGF.
Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USA.
Renan
R
Aguilar-Valenzuela
Eric D
ED
Carlsen
Yuejin
Y
Liang
Lynn
L
Soong
Jiaren
J
Sun
D000208:Acute Disease; D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes; D002478:Cells, Cultured; D054370:Chemokine CXCL9 / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D015870:Gene Expression; D006524:Hepatitis, Viral, Animal / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology / Q000821:virology; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000276:immunology* / Q000473:pathology / Q000821:virology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D019013:CD40 Antigens; D054370:Chemokine CXCL9; D018836:Inflammation Mediators; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D017228:Hepatocyte Growth Factor; D007371:Interferon-gamma
T cell inhibition; dendritic cells; hepatocyte growth factor; viral hepatitis