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Published online before print August 31, 2004

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(Journal of Leukocyte Biology. 2004;76:1171-1179.)
© 2004 by Society for Leukocyte Biology

Natural killer cells inhibit hepatitis C virus expression

Division of Allergy & Immunology, Joseph Stokes Jr. Research Institute at The Children’s Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine

¹ Correspondence: Division of Allergy & Immunology, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, 34th Street & Civic Center Blvd., Philadelphia, PA 19104. E-mail: ho{at}email.chop.edu

Natural killer (NK) cells are critical in host innate defense against certain viruses. The role of NK cells in controlling hepatitis C virus (HCV) remains obscure. We examined whether NK cells are capable of inhibiting HCV expression in human hepatic cells. When NK cells are cultured with the HCV replicon-containing hepatic cells, they have no direct cytolytic effect but release soluble factor(s) suppressing HCV RNA expression. Media conditioned by NK cell lines (NK-92 and YTS) or primary NK cells isolated from healthy donors contain interferon (IFN-) and potently inhibit HCV RNA expression. Ligation of CD81 on NK cells inhibits IFN- production and results in decreased anti-HCV activity. In addition, the antibodies to IFN- or IFN- receptors abolish the anti-HCV activity of NK cell-conditioned media. The role of IFN- in NK cell-mediated, anti-HCV activity is supported by the observation that NK cell-conditioned media enhanced expression of signal transducer and activator of transcription-1, a nuclear factor that is essential in IFN--mediated antiviral pathways. NK cell-conditioned media have the ability to stimulate intracellular IFN- expression in the hepatic cells, suggesting a mechanism responsible for NK cell-mediated, anti-HCV activity. Thus, NK cells hold the potential to play a vital role in controlling HCV replication in hepatic cells using an IFN--dependent mechanism.

Key Words: interferon • CD81 • STAT

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