Dunn, C;
Brunetto, M;
Reynolds, G;
Christophides, T;
Kennedy, PT;
Lampertico, P;
Das, A;
... Maini, MK; + view all
(2007)
Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage.
J EXP MED
, 204
(3)
667 - 680.
10.1084/jem.20061287.
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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.
| Type: | Article |
|---|---|
| Title: | Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1084/jem.20061287 |
| Publisher version: | http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC21379... |
| Keywords: | NATURAL-KILLER-CELLS, TRAIL-INDUCED APOPTOSIS, IFN-ALPHA-BETA, T-CELLS, IN-VIVO, TUMORICIDAL ACTIVITY, HUMAN HEPATOCYTES, VIRAL CLEARANCE, TNF FAMILY, LIGAND |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/7082 |
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