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J Hepatol. 2013 Oct;59(4):701-8. doi: 10.1016/j.jhep.2013.06.001. Epub 2013 Jun 12.

Independent, parallel pathways to CXCL10 induction in HCV-infected hepatocytes.

Author information

1
Department of Global Health, Pathobiology Program, University of Washington, Seattle, WA, United States.

Abstract

BACKGROUND & AIMS:

The pro-inflammatory chemokine CXCL10 is induced by HCV infection in vitro and in vivo, and is associated with outcome of IFN (interferon)-based therapy. We studied how hepatocyte sensing of early HCV infection via TLR3 (Toll-like receptor 3) and RIG-I (retinoic acid inducible gene I) led to expression of CXCL10.

METHODS:

CXCL10, type I IFN, and type III IFN mRNAs and proteins were measured in PHH (primary human hepatocytes) and hepatocyte lines harboring functional or non-functional TLR3 and RIG-I pathways following HCV infection or exposure to receptor-specific stimuli.

RESULTS:

HuH7 human hepatoma cells expressing both TLR3 and RIG-I produced maximal CXCL10 during early HCV infection. Neutralization of type I and type III IFNs had no impact on virus-induced CXCL10 expression in TLR3+/RIG-I+ HuH7 cells, but reduced CXCL10 expression in PHH. PHH cultures were positive for monocyte, macrophage, and dendritic cell mRNAs. Immunodepletion of non-parenchymal cells (NPCs) eliminated marker expression in PHH cultures, which then showed no IFN requirement for CXCL10 induction during HCV infection. Immunofluorescence studies also revealed a positive correlation between intracellular HCV Core and CXCL10 protein expression (r(2) = 0.88, p ≤ 0.001).

CONCLUSIONS:

While CXCL10 induction in hepatocytes during the initial phase of HCV infection is independent of hepatocyte-derived type I and type III IFNs, NPC-derived IFNs contribute to CXCL10 induction during HCV infection in PHH cultures.

KEYWORDS:

AP-1; HCV; IFIT1; IFN; IFN-induced protein with tetratricopeptide repeats 1; IRF; ISG; ISRE; KCs; Kupffer cells; LSECs; MAVS; MOI; NF-κB; NK; NPCs; Non-parenchymal cells; PAMP; PHH; PRR; RIG-I; STAT; TIR-domain-containing adapter-inducing IFN-β; TLR3; TNF-α; TRIF; Toll-like receptor 3; Type I interferon; Type III interferon; activator protein-1; hepatitis C virus; interferon; interferon regulatory factor; interferon stimulated gene; interferon stimulated response element; liver sinusoidal endothelial cells; mitochondrial antiviral-signaling protein; multiplicity of infection; natural killer; non-parenchymal cells; nuclear factor-κB; pathogen associated molecular pattern; pattern recognition receptor; primary human hepatocytes; retinoic acid inducible gene I; signal transducer and activator of transcription; tumor necrosis factor α

PMID:
23770038
PMCID:
PMC3779522
DOI:
10.1016/j.jhep.2013.06.001
[Indexed for MEDLINE]
Free PMC Article
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