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Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation.
- Source :
-
Gastroenterology [Gastroenterology] 2004 Nov; Vol. 127 (5), pp. 1513-24. - Publication Year :
- 2004
-
Abstract
- Background and Aims: Recent evidence suggests that toll-like receptors (TLRs) recognize certain viruses. We reported that hepatitis C virus (HCV) core and nonstructural 3 (NS3) proteins activate inflammatory pathways in monocytes. The aim of this study was to investigate the role of TLRs in innate immune cell activation by core and NS3 proteins.<br />Methods: Human monocytes, human embryonic kidney cells transfected with TLR2, and peritoneal macrophages from TLR2, MyD88 knockout, and wild-type mice were studied to determine intracellular signaling and proinflammatory cytokine induction by HCV proteins.<br />Results: HCV core and NS3 proteins triggered inflammatory cell activation via the pattern recognition receptor TLR2 and failed to activate macrophages from TLR2 or MyD88-deficient mice. HCV core and NS3 induced interleukin (IL)-1 receptor-associated kinase (IRAK) activity, phosphorylation of p38, extracellular regulated (ERK), and c-jun N-terminal (JNK) kinases and induced AP-1 activation. Activation of nuclear factor-kappaB by core and NS3 was associated with increased IkappaBalpha phosphorylation. TLR2-mediated cell activation was dependent on the conformation of core and NS3 proteins and required sequences in the regions of aa 2-122 in core and aa 1450-1643 in NS3. Although cellular uptake of core and NS3 proteins was independent of TLR2 expression, cell activation required TLR2. HCV core protein and TLR2 showed intracellular colocalization. The hyper-elevated TNF-alpha induction by TLR2 ligands in monocytes of HCV-infected patients was not due to increased TLR2 expression.<br />Conclusions: HCV core and NS3 proteins trigger inflammatory pathways via TLR2 that may affect viral recognition and contribute to activation of the innate immune system.
- Subjects :
- Animals
Cell Line
Hepatitis C pathology
Hepatitis C physiopathology
Hepatitis C, Chronic physiopathology
Humans
Inflammation virology
Kidney
Membrane Glycoproteins deficiency
Membrane Glycoproteins genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Monocytes
Receptors, Cell Surface deficiency
Receptors, Cell Surface genetics
Recombinant Proteins metabolism
Toll-Like Receptor 2
Toll-Like Receptors
Transfection
Hepacivirus physiology
Membrane Glycoproteins physiology
Receptors, Cell Surface physiology
Viral Core Proteins physiology
Viral Nonstructural Proteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0016-5085
- Volume :
- 127
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 15521019
- Full Text :
- https://doi.org/10.1053/j.gastro.2004.08.067