Viral and Host Factors Induce Macrophage Activation and Loss of Toll-Like Receptor Tolerance in Chronic HCV Infection

Angela Dolganiuc, Oxana Norkina, Karen Kodys, Donna Catalano, Gennadiy Bakis, Christopher Marshall, Pranoti Mandrekar, Gyongyi Szabo

Research output: Contribution to journalArticle

159 Scopus citations

Abstract

Background & Aims: Persistent inflammation contributes to progression of liver damage in chronic HCV (cHCV) infection. Repeated exposure to toll-like receptor (TLR) ligands results in tolerance, a protective mechanism aimed at limiting inflammation. Methods: Monocytes/macrophages were repeatedly stimulated via proinflammatory cytokine-inducing TLRs and evaluated for activation markers. Results: Unlike monocytes of controls or patients with nonalcoholic steatohepatitis, the monocytes of cHCV patients were hyperresponsive and failed to show homo- or heterotolerance to TLR ligands, manifested by elevated tumor necrosis factor (TNF)-α production. Serum levels of interferon (IFN)-γ, endotoxin (TLR4 ligand), and HCV core protein (TLR2 ligand) were elevated in cHCV patients suggesting potential mechanisms for in vivo monocyte preactivation. Treatment of normal monocytes with IFN-γ resulted in loss of tolerance to lipopolysaccharide (LPS) or HCV core protein. Furthermore, we found increased levels of MyD88-IRAK1 complexes and nuclear factor (NF)-κB activity both in monocytes of cHCV patients and in normal monocytes that lost TLR tolerance after IFN-γ + LPS pretreatment. In vitro differentiation of TLR non-tolerant cHCV monocytes into macrophages restored their capacity to exhibit TLR tolerance to LPS and HCV core protein, and this could be reversed by administration of IFN-γ. cHCV patients exhibited increased TNF-α in the circulation and in the liver. In cHCV livers, we found Kupffer cell/macrophage activation indicated by increased CD163 and CD33 expression. Conclusions: We identified that host-derived factors (IFN-γ and endotoxin) and viral factors (HCV core protein) act in tandem to induce and maintain monocyte/macrophage activation, thus favoring persistent inflammation in patients with cHCV infection.

Original languageEnglish (US)
Pages (from-to)1627-1636
Number of pages10
JournalGastroenterology
Volume133
Issue number5
DOIs
StatePublished - Nov 2007

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Dolganiuc, A., Norkina, O., Kodys, K., Catalano, D., Bakis, G., Marshall, C., Mandrekar, P., & Szabo, G. (2007). Viral and Host Factors Induce Macrophage Activation and Loss of Toll-Like Receptor Tolerance in Chronic HCV Infection. Gastroenterology, 133(5), 1627-1636. https://doi.org/10.1053/j.gastro.2007.08.003