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Journal of Virology, June 2000, p. 5525-5533, Vol. 74, No. 12
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Endotoxin Stimulates Liver Macrophages To Release Mediators That Inhibit an Early Step in Hepadnavirus Replication

Uta Klöcker,1 Ursula Schultz,2 Heinz Schaller,1 and Ulrike Protzer1,*

Zentrum für Molekulare Biologie Heidelberg (ZMBH), University of Heidelberg, D-69120 Heidelberg,1 and University Hospital, Department of Internal Medicine II/Molecular Biology, University of Freiburg,2 D-79106 Freiburg, Federal Republic of Germany

Received 10 December 1999/Accepted 27 March 2000

Hepadnaviruses are known to be sensitive to various extracellular mediators. Therefore, bacterial endotoxin, which induces the secretion of proinflammatory mediators in the liver, was studied for its effect on hepadnavirus infection in vitro using the duck hepatitis B virus (DHBV) model. In initial experiments, endotoxin was shown to inhibit DHBV replication in primary duck hepatocyte cultures prepared by standard collagenase perfusion. As a primary endotoxin target, hepatic nonparenchymal cells (NPC) contaminating primary hepatocyte cultures, and among these probably macrophages (Kupffer cells), were identified to secrete polypeptide mediators into the cell culture medium. When added during DHBV infection, these mediators elicited the principal antiviral effect in a dose-dependent fashion. On the molecular level, they inhibited accumulation of viral proteins as well as amplification of the nuclear extrachromosomal DHBV DNA templates. In hepatocytes with an established DHBV infection, DHBV protein and progeny virus production was inhibited while the levels of established nuclear DHBV DNA templates and viral transcripts remained unaffected. Finally, in hepatocytes infected with a replication-deficient recombinant DHBV-green fluorescent protein (GFP) virus, the endotoxin-induced mediators markedly reduced GFP expression from chimeric DHBV-GFP transcripts, indicating that the major effect is at a level of translation of viral RNAs. Taken together, the data obtained demonstrate that antiviral mediators, and among these the cytokines alpha interferon (IFN-alpha ) and IFN-gamma , are released from hepatic NPC, most probably liver macrophages, upon endotoxin stimulation; furthermore, these mediators act at a posttranscriptional step of hepadnavirus replication.

* Corresponding author. Mailing address: ZMBH, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany. Phone: 49-69221-546830. Fax: 49-69221-545893. E-mail: u.protzer{at}zmbh.uni-heidelberg.de.

Journal of Virology, June 2000, p. 5525-5533, Vol. 74, No. 12
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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