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

2007/03/12 by Claire Dunn, Maurizia Brunetto, Maurizia Rossana Brunetto +19 · 419 citations
Immunology and Microbiology · Medicine · #Apoptosis #Biology #Cytokine #Hepatitis B Virus Studies #Hepatitis B virus #Hepatocyte #Immune Cell Function and Interaction #Immune system #Immunology #In vitro #Inflammation #Innate immune system #Interferon #Interleukin #Tumor necrosis factor alpha #Viral gastroenteritis research and epidemiology #Virus

paper · pdf · doi:10.1084/jem.20061287

published in The Journal of Experimental Medicine 204(3), 667-680 (Rockefeller University Press)

openalex publication_date 2007/03/12 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/22

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.

Citations

• Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens. Implications for hepatitis B e antigen seroconversion.

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