Background: Kupffer cells and related cytokines are thought to play a critical role in liver fibrosis; however, the role played by Kupffer cells in hepatitis 13 virus-related fibrogenesis is unknown. Methods: Primary rat Kupffer cells were cultured with different titres of hepatitis B virus particles and the concentrations of transforming growth factor (TGF)-beta 1, interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-alpha in the culture supernatant were measured every 24h 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. Results: Kupffer cells maintained normal morphology and function throughout the 7-day exposure to hepatitis B virus. The concentration of TGF-beta 1 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-beta 1 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-1 and TNF-alpha) was unchanged throughout the experiment. Conclusion: Hepatitis B virus preferentially stimulates Kupffer cells to produce the pro-fibrogenic/anti-inflammatory cytokine TGF-beta 1 rather than the pro-inflammatory cytokines IL-6. IL-1 and TNF-alpha. This may partly explain why overt liver fibrosis still presents in cases of chronic hepatitis B virus infection with minimal (or no) necro-inflammation. (C) 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.