Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage.
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.
Dunn
Claire
C
Division of Infection and Immunity, University College London, London W1T 4JF, UK.
Brunetto
Maurizia
M
Reynolds
Gary
G
Christophides
Theodoros
T
Kennedy
Patrick T
PT
Lampertico
Pietro
P
Das
Abhishek
A
Lopes
A Ross
AR
Borrow
Persephone
P
Williams
Kevin
K
Humphreys
Elizabeth
E
Afford
Simon
S
Adams
David H
DH
Bertoletti
Antonio
A
Maini
Mala K
MK
D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000502:physiology*; D006515:Hepatitis B virus / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology* / Q000821:virology; D008099:Liver / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D008137:Longitudinal Studies; D015398:Signal Transduction / Q000276:immunology*
D016207:Cytokines; D016898:Interferon-alpha; D016209:Interleukin-8