Sensitization of Human Hepatic Stellate Cells to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis by Leflunomide

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During the resolution phase of hepatic fibrosis, a crucial mechanism is the apoptosis of activated hepatic stellate cells (HSCs). It is necessary to find more anti-fibrosis drugs that would modulate HSCs to be more susceptible to apoptotic stimuli. Here we showed that A771726, the active metabolite of leflunomide, markedly enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in the human hepatic stellate cell line LX-2. A771726 could increase caspase activity in LX-2 cells in a dose-dependent manner. A771726 did not increase the expression of TRAIL receptors in LX-2 cells but could inhibit activation of the c-Jun NH2-terminal kinase (JNK) pathway through decreasing TRAIL-induced JNK and c-Jun phosphorylation. Moreover, A771726 could accelerate TRAIL-induced apoptosis via inhibiting nuclear factor-kappaB (NF-κB) activation in LX-2 cells. In conclusion, our results indicated leflunomide could enhance the sensitivity of LX-2 cells to TRAIL-induced apoptosis via inhibiting the survival pathways and provided a promising approach to anti-fibrotic therapy with leflunomide.