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

Gastroenterology. 2004 Nov;127(5):1513-24. doi: 10.1053/j.gastro.2004.08.067.


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.

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-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.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Hepacivirus / physiology*
  • Hepatitis C / pathology
  • Hepatitis C / physiopathology
  • Hepatitis C, Chronic / physiopathology
  • Humans
  • Inflammation / virology
  • Kidney
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / physiology*
  • Recombinant Proteins / metabolism
  • Toll-Like Receptor 2
  • Toll-Like Receptors
  • Transfection
  • Viral Core Proteins / physiology*
  • Viral Nonstructural Proteins / physiology*


  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • Recombinant Proteins
  • TLR2 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptors
  • Viral Core Proteins
  • Viral Nonstructural Proteins