Drug induced liver injury (DILI) is an idiosyncratic adverse drug reaction
leading to severe liver damage. Kupffer cells (KC) sense hepatic tissue
stress/damage and therefore could be a tool for the estimation of consequent
effects associated with DILI. Aim of the present study was to establish a
human in vitro liver model for the investigation of immune-mediated signaling
in the pathogenesis of DILI. Hepatocytes and KC were isolated from human liver
specimens. The isolated KC yield was cells/g liver tissue with a purity of
>80%. KC activation was investigated by the measurement of reactive oxygen
intermediates (ROI, DCF assay) and cell activity (XTT assay). The initial KC
activation levels showed broad donor variability. Additional activation of KC
using supernatants of hepatocytes treated with hepatotoxic drugs increased KC
activity and led to donor-dependent changes in the formation of ROI compared
to KC incubated with supernatants from untreated hepatocytes. Additionally, a
compound- and donor-dependent increase in proinflammatory cytokines or in
anti-inflammatory cytokines was detected. In conclusion, KC related immune
signaling in hepatotoxicity was successfully determined in a newly established
in vitro liver model. KC were able to detect hepatocyte stress/damage and to
transmit a donor- and compound-dependent immune response via cytokine
production
