Basic–Liver, Pancreas, and Biliary TractViral and Host Factors Induce Macrophage Activation and Loss of Toll-Like Receptor Tolerance in Chronic HCV Infection
Section snippets
Reagents
LPS was from List Biological Laboratories (Campbell, CA), peptidoglycan (PGN) from Fluka (Milwaukee, WI), Pam2CSK4 and Pam3CSK4 from EMC Microcollections (Tuebingen, Germany), Gardiquimod from Invivogen (San Diego, CA), fetal calf serum (FCS) from HyClone (Logan, UT), RPMI 1640 from Gibco (Grand Island, NY), recombinant HCV core protein (genotype 1A aa 2–192) from Biodesign (Saco, MN).
Patients and Cells
The study was approved by the Committee for the Protection of Human Subjects in Research at the University of
Monocytes of cHCV Patients Lack Tolerance to TNF-α-Inducing TLR Ligands
We have previously reported that monocytes of cHCV patients produced significantly higher levels of TNF-α both at baseline and upon stimulation with TLR4 and TLR2 ligands compared with controls.6 Production of TNF-α by immune cells contributes to the efficient control of invading pathogens, whereas excessive and uncontrolled production may lead to systemic chronic inflammation.2, 3 Tolerance to TLR ligands is one of the protective mechanisms against chronic inflammation.10 Considering the
Discussion
This study has provided 3 key observations related to the inflammatory cell activation during cHCV infection. First, we identified that monocytes, the precursors of tissue macrophages, are preactivated in patients with chronic HCV infection. Second, we demonstrated that in vivo occurring concentrations of IFN-γ, endotoxin, and HCV core protein modulate monocyte functions and favor the increased frequency of MyD88/IRAK complexes, elevated NF-κB activation, and excessive TNF-α production seen in
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Supported by NIAAAA grant AA11576 (to G.S.), PHS grant AA12862, UMass CFAR grant 5P30 AI42845, and PHS grant DK32520.
The authors have no conflicts of interest to disclose.