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

• Published in: Journal of hepatology 2013-10, Vol.59 (4), p.701-708
• Main Authors: Brownell, Jessica, Wagoner, Jessica, Lovelace, Erica S, Thirstrup, Derek, Mohar, Isaac, Smith, Wesley, Giugliano, Silvia, Li, Kui, Crispe, I. Nicholas, Rosen, Hugo R, Polyak, Stephen J
• Format: Article
• Language: English
• Subjects: Cell Line; Chemokine CXCL10 - biosynthesis; Chemokine CXCL10 - genetics; DEAD Box Protein 58; DEAD-box RNA Helicases - metabolism; Gastroenterology and Hepatology; HCV; Hepacivirus - immunology; Hepacivirus - pathogenicity; Hepatitis C, Chronic - genetics; Hepatitis C, Chronic - immunology; Hepatitis C, Chronic - metabolism; Hepatocytes - immunology; Hepatocytes - metabolism; Hepatocytes - virology; Humans; Interferons - antagonists & inhibitors; Interferons - genetics; Interferons - metabolism; Neutralization Tests; Non-parenchymal cells; Receptors, Immunologic; RIG-I; RNA, Messenger - genetics; RNA, Messenger - metabolism; TLR3; Toll-Like Receptor 3 - metabolism; Type I interferon; Type III interferon
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2013.06.001

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 (r2 = 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.