Hepatitis B virus particles preferably induce Kupffer cells to produce TGF-β1 over pro-inflammatory cytokines

BackgroundKupffer cells and related cytokines are thought to play a critical role in liver fibrosis; however, the role played by Kupffer cells in hepatitis B virus-related fibrogenesis is unknown.MethodsPrimary rat Kupffer cells were cultured with different titres of hepatitis B virus particles and the concentrations of transforming growth factor (TGF)-β1, interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-α in the culture supernatant were measured every 24 h for 7 days. The mRNA and protein levels of these cytokines in Kupffer cells were also analysed using quantitative real-time polymerase chain reaction and western blotting, respectively.ResultsKupffer cells maintained normal morphology and function throughout the 7-day exposure to hepatitis B virus. The concentration of TGF-β1 secreted by hepatitis B virus-stimulated Kupffer cells (6 log IU/ml hepatitis B virus) increased 5.38- and 7.75-fold by Days 3 and 7, respectively (p < 0.01). Western blotting showed that TGF-β1 expression in Kupffer cells exposed to high titres of hepatitis B virus increased 1.80- and 2.42-fold by Days 3 and 7, respectively (p < 0.01). In contrast, Kupffer cell expression and secretion of pro-inflammatory cytokines (IL-6, IL-1 and TNF-α) was unchanged throughout the experiment.ConclusionHepatitis B virus preferentially stimulates Kupffer cells to produce the pro-fibrogenic/anti-inflammatory cytokine TGF-β1 rather than the pro-inflammatory cytokines IL-6, IL-1 and TNF-α. This may partly explain why overt liver fibrosis still presents in cases of chronic hepatitis B virus infection with minimal (or no) necro-inflammation.