Liver Cell Regulation Mechanism Of Erythropoietin Biological Role

Hepatopoietin (HPO) is closely related to liver regeneration. In this paper, we identified that it can interact with macrophage migration inhibitory factor (MIF) and thioredoxin (TRX), and investigated the effect of their interaction on the activity of HPO, the result is as follows:MIF is a proinflammatory cytokine and has the activity of reductase, which is involved in the regulation of cell proliferation and apoptosis. Our research showed that rMIF added to the cell could promote the proliferation of HepG2 dependent on the concentration. Overexpressed MIF in cytoplasm could enhanced the activity of HPO promoter. The signal transduction of MIF in cytoplasm mediated by JAB1 might inhibit the proliferation of HepG2, as JAB1 antisense could increase the activity of HPO promoter. The physical interaction between HPO and MIF was detected in vitro and in vivo. MIF decreased the potentiation role of HPO on AP-1. MIF and HPO bind to the same region in JAB1, but the conserved sequence (NES) of JAB 1 has different influence on their binding.MIF acts as a redox enzyme in cytoplasm and interacts with HPO , which indicated HPO could be affected by redox state in environment. Further experiments showed that HPO is very sensitive to oxidative stress and can be assembled into dimer under the stimulation of oxidant. HPO could interact with TRX in vitro and in vivo, which is the critical cytokine in redox regulation. HPO could transfer the disulfide directly to TRX in vitro and oxidized TRX in vivo. As a result, the activity of redox sensitive transcription factor AP-1 and NF-κB were increased.Taken together, HPO play an important role in regulating the cell redox state and could modulate the proliferation of hepatocyte by interacting with MIF and TRX.