Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation

Angela Dolganiuc, Shilpa Oak, Karen Kodys, Douglas T. Golenbock, Robert W. Finberg, Evelyn Kurt-Jones, G. Szabó

Research output: Contribution to journalArticle

233 Citations (Scopus)

Abstract

Background & 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. 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. 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-κB by core and NS3 was associated with increased IκBα 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-α induction by TLR2 ligands in monocytes of HCV-infected patients was not due to increased TLR2 expression. 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.

Original languageEnglish
Pages (from-to)1513-1524
Number of pages12
JournalGastroenterology
Volume127
Issue number5
DOIs
Publication statusPublished - Nov 2004

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Toll-Like Receptor 2
Hepatitis C
Hepacivirus
Proteins
Monocytes
Toll-Like Receptors
Interleukin-1 Receptor-Associated Kinases
Phosphorylation
MAP Kinase Kinase 4
Pattern Recognition Receptors
JNK Mitogen-Activated Protein Kinases
Transcription Factor AP-1
Peritoneal Macrophages
Knockout Mice
Immune System
Macrophages
Cytokines
Ligands
Viruses
Kidney

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation. / Dolganiuc, Angela; Oak, Shilpa; Kodys, Karen; Golenbock, Douglas T.; Finberg, Robert W.; Kurt-Jones, Evelyn; Szabó, G.

In: Gastroenterology, Vol. 127, No. 5, 11.2004, p. 1513-1524.

Research output: Contribution to journalArticle

Dolganiuc, Angela ; Oak, Shilpa ; Kodys, Karen ; Golenbock, Douglas T. ; Finberg, Robert W. ; Kurt-Jones, Evelyn ; Szabó, G. / Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation. In: Gastroenterology. 2004 ; Vol. 127, No. 5. pp. 1513-1524.
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