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J. Biol. Chem., Vol. 280, Issue 17, 16739-16747, April 29, 2005

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Distinct Poly(I-C) and Virus-activated Signaling Pathways Leading to Interferon- Production in Hepatocytes^*

Kui Li, Zihong Chen, Nobuyuki Kato¶, Michael Gale, Jr.||, and Stanley M. Lemon**

From the Department of Microbiology and Immunology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas 77555-1019, the ^¶Department of Molecular Biology, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan, and the ^||Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9048

Innate cellular antiviral defenses are likely to influence the outcome of infections by many human viruses, including hepatitis B and C viruses, agents that frequently establish persistent infection leading to chronic hepatitis, cirrhosis, and liver cancer. However, little is known of the pathways by which hepatocytes, the cell type within which these hepatitis agents replicate, sense infection, and initiate protective responses. We show that cultured hepatoma cells, including Huh7 cells, do not activate the interferon (IFN)- promoter in response to extracellular poly(I-C). In contrast, the addition of poly(I-C) to culture media activates the IFN- promoter and results in robust expression of IFN-stimulated genes (ISG) in PH5CH8 cells, which are derived from non-neoplastic hepatocytes transformed with large T antigen. Small interfering RNA knockdown of TLR3 or its adaptor, Toll-interleukin-1 receptor domain-containing adaptor inducing IFN- (TRIF), blocked extracellular poly(I-C) signaling in PH5CH8 cells, whereas poly(I-C) responsiveness could be conferred on Huh7 hepatoma cells by ectopic expression of Toll-like receptor 3 (TLR3). In contrast to poly(I-C), both cell types signal the presence of Sendai virus infection through a TLR3-independent intracellular pathway requiring expression of retinoic acid-inducible gene I (RIG-I), a putative cellular RNA helicase. Silencing of RIG-I expression impaired only the response to Sendai virus and not extracellular poly(I-C). We conclude that hepatocytes contain two distinct antiviral signaling pathways leading to expression of type I IFNs, one dependent upon TLR3 and the other dependent on RIG-I, with little cross-talk between these pathways.

Received for publication, December 16, 2004 , and in revised form, February 28, 2005.

^* This work was supported in part by National Institutes of Health Grants R21-DA018054 (to K. L.), U19-AI40035 (to S. M. L.), U01-AI48235 (to M. G.), and in part by Gastrointestinal Research Interdisciplinary Program Seed Money (to K. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence may be addressed: Institute for Human Infections and Immunity, The University of Texas Medical Branch at Galveston, 301 University Blvd., Galveston, TX 77555-0428. Tel.: 409-747-6500; Fax: 409-747-6514; E-mail: smlemon{at}utmb.edu. John Mitchell Hemophilia of Georgia Liver Scholar of the American Liver Foundation. To whom correspondence may be addressed: 4.168A Medical Research Bldg., University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1019. Tel.: 409-772-4928; Fax: 409-772-5065; E-mail: kuli{at}utmb.edu.

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