Toll-like receptor-stimulated non-parenchymal liver cells can regulate hepatitis C virus replication.
OBJECTIVE
The aim of this study was to further elucidate the role of the IFN and the Toll-like receptor (TLR) system in the control of HCV replication by non-parenchymal liver cells (NPC).


METHODS
Murine HCV replicon bearing MH1 cells were incubated with supernatants from TLR1-9-stimulated murine NPC (Kupffer cells (KC), liver sinusoidal endothelial cells (LSEC)) and bone marrow-derived myeloid dendritic cells (mDC). HCV replication and expression of IFN-stimulated genes (ISGs) as well as TLR1-9 mRNA were determined by real-time rtPCR.


RESULTS
IFNs (-alpha, -beta, -gamma) and TLR3 ligands only (despite the expression of TLR1-7 and TLR9 mRNA) achieved direct suppression of HCV replication by about 80-90% or 60%, respectively. Supernatants from TLR3- and 4-stimulated NPC only, however, led to potent suppression of HCV replication through IFN-beta and induction of ISGs. By contrast, mDCs could be stimulated by TLR2, -3, -4, -7 and -9 to produce antiviral cytokines.


CONCLUSIONS
TLR3- and TLR4-stimulated NPC are able to regulate HCV replication through production of IFN-beta. This can also, at least partly explain the high level of ISG expression in HCV infected livers. These novel findings are of particular relevance for the control of HCV replication by the innate immune system of the liver.
Broering
Ruth
R
Department of Gastroenterology and Hepatology, University Hospital of Essen, Hufelandstrasse 55, 45122 Essen, Germany.
Wu
Jun
J
Meng
Zhongji
Z
Hilgard
Philip
P
Lu
Mengji
M
Trippler
Martin
M
Szczeponek
Agnes
A
Gerken
Guido
G
Schlaak
Joerg F
JF
D000818:Animals; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D016174:Hepacivirus / Q000502:physiology*; D007107:Immune System / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D007728:Kupffer Cells / Q000166:cytology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*
D012333:RNA, Messenger; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D016899:Interferon-beta