Dendritic Cells as a Novel Target for Erythropoietin: Studies in Murine Models.

Erythropoietin (EPO) is the major hormone that promotes the proliferation and differentiation of erythroid progenitor cells. Unexpectedly, EPO receptor (EPO-R) was also found on non-erythroid cells; thus leading to the discovery of non-erythroid effects of EPO. Our own previous contribution to that issue was in demonstrating that the immune system is a target for EPO, including both the cellular and humoral immune response types. As yet, the direct target cells for EPO as well as the molecular mechanisms underlying its function as an immunomodulator remain unknown. We first examined lymphocytes as possible candidates, and could not detect any expression of EPO-Rs on these cells. Here, we focused on dendritic cells (DCs), known to initiate immune response as antigen presenting and T cell priming cells. We employed murine bone marrow DCs (BMDCs) and splenic DCs (SDCs) models to determine EPO-R expression, and delineate in-vitro and in-vivo effects of EPO via these cells. We found that BMDCs express EPO-R mRNA, as detected by RT-PCR. In vitro stimulation of the BMDCs with recombinant human EPO (rHuEPO) activated the NFkB and MAPK signaling pathways, and induced a higher surface expression of CD80, CD86 and MHC class II. These data are reinforced by in vivo experiments, showing that rHuEPO injection into naïve mice led to an increase in the SDC population and in the cell surface expression of CD80, CD86 and MHC class II markers. These novel findings implicate the significance of the multifunctional role of EPO in the hematopoietic and immune systems, and may lead to its further clinical applications as an immunomodulator.