Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 133; no. 5; p. 1627
• Main Authors: Dolganiuc, Angela, Norkina, Oxana, Kodys, Karen, Catalano, Donna, Bakis, Gennadiy, Marshall, Christopher, Mandrekar, Pranoti, Szabo, Gyongyi
• Format: Journal Article
• Language: English
• Published: United States 01.11.2007
• Subjects: Adult; Case-Control Studies; Endotoxins - blood; Endotoxins - pharmacology; Female; Hepacivirus - metabolism; Hepatitis C, Chronic - blood; Hepatitis C, Chronic - immunology; Humans; Inflammation - metabolism; Inflammation - pathology; Interferon-gamma - blood; Interferon-gamma - pharmacology; Kupffer Cells - drug effects; Kupffer Cells - metabolism; Kupffer Cells - pathology; Ligands; Lipopolysaccharides - pharmacology; Macrophage Activation - drug effects; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; Male; Middle Aged; Monocytes - drug effects; Monocytes - metabolism; Monocytes - pathology; NF-kappa B - metabolism; Toll-Like Receptor 2 - blood; Toll-Like Receptor 4 - blood; Toll-Like Receptors - immunology; Tumor Necrosis Factor-alpha - metabolism; Viral Core Proteins - blood; Viral Core Proteins - pharmacology
• ISSN: 1528-0012
• DOI: 10.1053/j.gastro.2007.08.003

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. Monocytes/macrophages were repeatedly stimulated via proinflammatory cytokine-inducing TLRs and evaluated for activation markers. 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)-alpha production. Serum levels of interferon (IFN)-gamma, 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-gamma 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)-kappaB activity both in monocytes of cHCV patients and in normal monocytes that lost TLR tolerance after IFN-gamma + 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-gamma. cHCV patients exhibited increased TNF-alpha in the circulation and in the liver. In cHCV livers, we found Kupffer cell/macrophage activation indicated by increased CD163 and CD33 expression. We identified that host-derived factors (IFN-gamma 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.