Adaptive unfolded protein response promotes cell survival in rifampicin-treated L02 cells

An important concept in drug-induced liver injury (DILI) is adaptation, which means the injury reverses with the continuation of the drug. The mechanism of adaption of drugs remains enigmatic, adaptive unfolded protein response (UPR) is possibly involved. We once observed adaptation phenomenon of rifampicin (RFP) in animal models, in this study, we investigate the effects of RFP on adaptive UPR in L02 cells, and after inhibiting UPR by using 4-phenylbutyrate (4-PBA), the change of cell viability and cell apoptosis in RFP-treated cells. We found that with the concentration of RFP increased and the treatment time was prolonged, the glucose-regulated protein 78 (GRP78), a hallmark of the UPR, was upregulated, and was dose- and time-dependent. RFP also activates the p-eukaryotic initiation factor 2α (eIF2α) protein expression. 4-PBA decreased GRP78 and p-eIF2α protein expression levels. Moreover, FCA showed that cell apoptosis rate obviously increased, and MTT assay showed that cell survival rate obviously decreased, this indicates that after inhibiting the UPR, the cell damage increased, which shows that the UPR is an adaptation mechanism to protect cells against injury induced by RFP. This also proves that when the degree of UPR induced by RFP is relatively mild, adaptive UPR is helpful for cell survival.