title: Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection.
abstract: OBJECTIVE
  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)-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Dolganiuc
authors.forename: Oxana
authors.initials: O
authors.lastname: Norkina
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.forename: Donna
authors.initials: D
authors.lastname: Catalano
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Bakis
authors.forename: Christopher
authors.initials: C
authors.lastname: Marshall
authors.forename: Pranoti
authors.initials: P
authors.lastname: Mandrekar
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D004731:Endotoxins / Q000097:blood / Q000494:pharmacology*; D005260:Female; D016174:Hepacivirus / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000097:blood / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000097:blood / Q000494:pharmacology*; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000097:blood; D051197:Toll-Like Receptor 4 / Q000097:blood; D051193:Toll-Like Receptors / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014758:Viral Core Proteins / Q000097:blood / Q000494:pharmacology*
chemical_list: D004731:Endotoxins; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins; D007371:Interferon-gamma