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Long‐term stimulation of T oll‐like receptor 3 in primary human hepatocytes leads to sensitization for antiviral responses induced by poly I : C treatment
Author(s) -
Broering R.,
Lutterbeck M.,
Trippler M.,
Kleinehr K.,
Poggenpohl L.,
Paul A.,
Gerken G.,
Schlaak J. F.
Publication year - 2014
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/jvh.12174
Subject(s) - interferon , pathogenesis , snp , sensitization , immunology , stimulation , hepatitis c , single nucleotide polymorphism , receptor , biology , gene , genotype , genetics , neuroscience
Summary Chronic hepatitis C infection is associated with increased expression of interferon‐sensitive genes ( ISGs ) in the liver, which is, paradoxically, correlated with the nonresponse to interferon ( IFN )‐based therapies. In the present study PHHs were isolated from HCV ‐infected or uninfected patients and stimulated with the TLR 1‐9 ligands for 6–24 h. Expression of cytokines and ISG s was determined by ELISA and qRT ‐ PCR . A comparative analysis was performed for TLR 3 signalling, which was also correlated with single nucleotide polymorphisms ( SNP s) related to HCV pathogenesis. TLR‐activated PHH s produced pro‐inflammatory and anti‐inflammatory cytokines, whereas IFN s were exclusively induced by TLR 3 stimulation. Here, IL ‐29 and IL ‐28 A were significantly highly expressed than IFN ‐α and IFN ‐β. TLR 3‐induced IFN response was enhanced in hepatocytes isolated from patients with HCV infection. This hyper‐responsiveness could be mimicked in naïve PHH s consistently stimulated with low dose of poly I : C , but not G uardiquimod. The higher responsiveness in PHH isolated from HCV ‐infected patients could be partially explained by higher frequencies of unfavourable SNP alleles of different SNP s associated with HCV progression and treatment outcome. These data suggest that durable activation of TLR 3 but not TLR 7, by low doses of viral replicative intermediates, increases the sensitivity to viral invasion. These findings shed new light on the relevance of TLR 3 in the pathogenesis of HCV and may provide a possible explanation for the increased ISG expression during chronic HCV infection, the so‐called IFN paradox.