Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3
Melanie Werner,
Stefan Schefczyk,
Martin Trippler,
Juergen W. Treckmann,
Hideo A. Baba,
Guido Gerken,
Joerg F. Schlaak,
Ruth Broering
Affiliations
Melanie Werner
Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
Stefan Schefczyk
Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
Martin Trippler
Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
Juergen W. Treckmann
Department of General-, Visceral- and Transplantation-Surgery, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
Hideo A. Baba
Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
Guido Gerken
Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
Joerg F. Schlaak
Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
Ruth Broering
Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1–9 ligands for 6–24 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-κB, AKT, JNK, p38 and ERK1/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection.
