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

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

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

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

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)-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.

Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection. Publishing Authors By Initials

A Dolganiuc,O Norkina,K Kodys,D Catalano,G Bakis,C Marshall,P Mandrekar,G Szabo,A Dolganiuc,O Norkina,K Kodys,D Catalano,G Bakis,C Marshall,P Mandrekar,G Szabo,

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

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Gastroenterology

VOLUME: 133

Page Numbers: 1627-36

Journal Abbreviation: Gastroenterology

ISSN: 1528-0012

DAY: 2

MONTH: 08

YEAR: 2007

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

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LANGUAGE: eng

NlmUniqueID: 374630

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Grant and Affiliation Information for Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection.

AFFILIATION: University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Country: United States

AGENCY: United States NIDDK

GRANT: DK32520

ACRONYM: DK

MEDLINETA: Gastroenterology

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