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Journal of Virology, November 2002, p. 10702-10707, Vol. 76, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.21.10702-10707.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Interleukin-18 Inhibits Hepatitis B Virus Replication in the Livers of Transgenic Mice{dagger}

Kiminori Kimura, Kazuhiro Kakimi, Stefan Wieland, Luca G. Guidotti, and Francis V. Chisari*

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

Received 13 May 2002/ Accepted 23 July 2002

Interleukin-18 (IL-18) produced by activated antigen-presenting cells stimulates natural killer (NK) cells, natural killer T (NKT) cells, and T cells to secrete gamma interferon (IFN-{gamma}). In this study, injection of a single 10-µg dose of recombinant murine IL-18 rapidly, reversibly, and noncytopathically inhibited hepatitis B virus (HBV) replication in the livers of HBV transgenic mice. Furthermore, HBV replication was inhibited by as little as 1 µg of IL-18 injected repetitively, and also by a single 0.1-µg dose of IL-18 injected together with 1 ng of IL-12, neither of which inhibited HBV replication individually, demonstrating synergy between these cytokines in this system. The antiviral effect of IL-18 was mediated by its ability to activate resident intrahepatic NK cells and NKT cells to produce IFN-{gamma} and by its ability to induce IFN-{alpha}/ß production in the liver. These results suggest that IL-18 has the potential to contribute to the control of HBV replication during self-limited infection and that it may have therapeutic value for the treatment of patients with chronic hepatitis.

* Corresponding author. Mailing address: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-8228. Fax: (858) 784-2160. E-mail: fchisari{at}scripps.edu.

{dagger} This is manuscript number 14979-MEM from The Scripps Research Institute.

Journal of Virology, November 2002, p. 10702-10707, Vol. 76, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.21.10702-10707.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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