TY - JOUR
T1 - Viral and Host Factors Induce Macrophage Activation and Loss of Toll-Like Receptor Tolerance in Chronic HCV Infection
AU - Dolganiuc, Angela
AU - Norkina, Oxana
AU - Kodys, Karen
AU - Catalano, Donna
AU - Bakis, Gennadiy
AU - Marshall, Christopher
AU - Mandrekar, Pranoti
AU - Szabo, Gyongyi
N1 - Funding Information:
Supported by NIAAAA grant AA11576 (to G.S.), PHS grant AA12862, UMass CFAR grant 5P30 AI42845, and PHS grant DK32520.
PY - 2007/11
Y1 - 2007/11
N2 - 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.
AB - 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.
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U2 - 10.1053/j.gastro.2007.08.003
DO - 10.1053/j.gastro.2007.08.003
M3 - Article
C2 - 17916356
AN - SCOPUS:35649007401
SN - 0016-5085
VL - 133
SP - 1627
EP - 1636
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -