Distinct poly(I-C) and virus-activated signaling pathways leading to interferon-β production in hepatocytes

Kui Li, Zihong Chen, Nobuyuki Kato, Michael Gale, Stanley M. Lemon

Research output: Contribution to journalArticle

255 Citations (Scopus)

Abstract

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)-β promoter in response to extracellular poly(I-C). In contrast, the addition of poly(I-C) to culture media activates the IFN-β 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-β (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.

Original languageEnglish (US)
Pages (from-to)16739-16747
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number17
DOIs
StatePublished - Apr 29 2005
Externally publishedYes

Fingerprint

Poly I-C
Viruses
Toll-Like Receptor 3
Interferons
Hepatocytes
Genes
Tretinoin
Sendai virus
Antiviral Agents
Hepatocellular Carcinoma
Infection
RNA Helicases
Interleukin-1 Receptors
Viral Tumor Antigens
Virus Diseases
Chronic Hepatitis
Liver Neoplasms
Hepatitis B virus
Hepacivirus
Liver

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Distinct poly(I-C) and virus-activated signaling pathways leading to interferon-β production in hepatocytes. / Li, Kui; Chen, Zihong; Kato, Nobuyuki; Gale, Michael; Lemon, Stanley M.

In: Journal of Biological Chemistry, Vol. 280, No. 17, 29.04.2005, p. 16739-16747.

Research output: Contribution to journalArticle

Li, Kui ; Chen, Zihong ; Kato, Nobuyuki ; Gale, Michael ; Lemon, Stanley M. / Distinct poly(I-C) and virus-activated signaling pathways leading to interferon-β production in hepatocytes. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 17. pp. 16739-16747.
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