Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage

Research output: Contribution to journalArticle

Authors

  • C Dunn
  • M Brunetto
  • G Reynolds
  • T Christophides
  • PT Kennedy
  • P Lampertico
  • [No Value] [No Value]
  • AR Lopes
  • P Borrow
  • KT Williams
  • A Bertoletti
  • MK Maini

Colleges, School and Institutes

Abstract

Hepatitis B virus (HBV) causes chronic infection in more than 350 million people worldwide. It replicates in hepatocytes but is non-cytopathic; liver damage is thought to be immune mediated. Here, we investigated the role of innate immune responses in mediating liver damage in patients with chronic HBV infection. Longitudinal analysis revealed a temporal correlation between flares of liver inflammation and fluctuations in interleukin (IL)-8, interferon (IFN)-alpha, and natural killer (NK) cell expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) directly ex vivo. A cross-sectional study confirmed these findings in patients with HBV-related liver inflammation compared with healthy carriers. Activated, TRAIL-expressing NK cells were further enriched in the liver of patients with chronic HBV infection, while their hepatocytes expressed increased levels of a TRAIL death-inducing receptor. IFN-alpha concentrations found in patients were capable of activating NK cells to induce TRAIL-mediated hepatocyte apoptosis in vitro. The pathogenic potential of this pathway could be further enhanced by the ability of the IFN-alpha/IL-8 combination to dysregulate the balance of death-inducing and regulatory TRAIL receptors expressed on hepatocytes. We conclude that NK cells may contribute to liver inflammation by TRAIL-mediated death of hepatocytes and demonstrate that this non-antigen-specific mechanism can be switched on by cytokines produced during active HBV infection.

Details

Original languageEnglish
Pages (from-to)667-680
Number of pages14
JournalThe Journal of Experimental Medicine
Volume204
Issue number3
Publication statusPublished - 20 Feb 2007