Autocrine function of erythropoietin in IGF-1-induced erythropoietin biosynthesis.

Insulin-like growth factor-1 (IGF-1) and erythropoietin (EPO) are induced in brain cells after brain ischemia and show synergistic neuroprotective effects. In LN215 astrocytoma cells, IGF-1 induced the activation of hypoxia-inducible factor-1, leading to increases in EPO mRNA levels and the secretion of EPO. Interestingly, blocking the potential action of secreted EPO on LN215 cells with EPO antibody, EPO receptor antibody, and soluble EPO receptor significantly suppressed the effect of IGF-1 on the biosynthesis of EPO. Synergistic action between IGF-1 and recombinant human EPO in the astrocytic production of EPO was observed. These data suggest that the IGF-1-EPO production/secretion process initiates a positive feedback loop of EPO biosynthesis in astrocytes, providing a molecular link between the two neuroprotective cytokines.