Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

Abstract

Erythropoietin (EPO) is the main hormone that promotes proliferation and differentiation of erythroid progenitor cells via binding to its surface receptor (EPO-R). Recent studies suggest that this hormone may affect also other cell types, besides the red blood cell lineage. We have previously demonstrated that the immune system is a target of EPO; however, the direct target cells of EPO, as well as the molecular mechanisms underlying its role as an immunomodulator, are unknown. Here we present evidence for functional effects of EPO on dendritic cells (DCs), which are known to initiate the immune response. In-vivo experiments in EPO-injected mice and in transgenic mice over-expressing human EPO showed an increased splenic DC population with a higher cell surface expression of CD80 and CD86. Further analysis based on mouse models, showed that DCs derived in-vitro from bone marrow (BM-DCs) express EPO-R mRNA. In-vitro stimulation of these DCs with recombinant human EPO enhanced viability, upregulated CD80, CD86 and MHC class II and augmented the secretion of IL-12. Biochemical analysis of EPO mediated signaling in the BM-DCs showed activation of the AKT, MAPK and NF-kappaB pathways. EPO stimulation of the BM-DCs led to Tyr-phosphorylation of STAT3. The inability to detect EPO mediated activation of STAT5 in the BM-DCs, suggests that in DCs, STAT3 may play a more important role than STAT5 in EPO-R signaling. Taken together, our data support the premise that DCs are direct targets of EPO, thereby providing an insight to the immunomodulatory functions of EPO.

Erythropoietin treatment leads to reduced blood glucose levels and body mass: insights from murine models

“…Hence, such functions include neuroprotection (Brines et al 2004, Cilloni et al 2004, anti-neoplastic activity (Mittelman et al 2001, Katz et al 2005, and improvement in congestive heart failure (Silverberg et al 2002, Fiordaliso et al 2005, Camici et al 2007. We (Prutchi-Sagiv et al 2006a,b, 2008, Ghezzi & Mengozzi 2007, Katz et al 2007, Lifshitz et al 2009), as well as others (Ghezzi & Mengozzi 2007), have found EPO-associated improvement in immunological functions.…”

Macrophages as novel target cells for erythropoietin

“…Our search for possible mechanisms of the immunomodulatory effects of EPO led us to the novel discovery that dendritic cells express the EPO-receptor, and that stimulation with EPO enhances their survival and function. 7,8 Studies in murine models showed that EPO increased the splenic dendritic cell population with a higher cell surface expression of the co-stimulatory molecules CD80 and CD86. 8 Further analysis carried out on bone marrow-derived dendritic cells led to the findings that the cells expressed EPOreceptor mRNA and that in-vitro stimulation of these cells enhanced the cells' viability, up-regulated CD80, CD86 and MHC class II expression, augmented the secretion of interleukin (IL)-12 and activated multiple signaling pathways.…”

“…7,8 Studies in murine models showed that EPO increased the splenic dendritic cell population with a higher cell surface expression of the co-stimulatory molecules CD80 and CD86. 8 Further analysis carried out on bone marrow-derived dendritic cells led to the findings that the cells expressed EPOreceptor mRNA and that in-vitro stimulation of these cells enhanced the cells' viability, up-regulated CD80, CD86 and MHC class II expression, augmented the secretion of interleukin (IL)-12 and activated multiple signaling pathways. 8 Based on these findings, we hypothesized that macrophages are also potential targets of EPO.…”

“…8 Further analysis carried out on bone marrow-derived dendritic cells led to the findings that the cells expressed EPOreceptor mRNA and that in-vitro stimulation of these cells enhanced the cells' viability, up-regulated CD80, CD86 and MHC class II expression, augmented the secretion of interleukin (IL)-12 and activated multiple signaling pathways. 8 Based on these findings, we hypothesized that macrophages are also potential targets of EPO. This would be an important discovery, since macrophages and dendritic cells have common progenitors, 9 and macrophages are also powerful antigen-presenting cells and serve as key effectors of the innate immune response.…”

Immunomodulation of Potent Antioxidant Agents: Preclinical Study to Clinical Application in Multiple Sclerosis

“…Interestingly, PI3K/Aktpathway-related responses to OS and apoptosis have also been shown to be mediated by the transcriptional regulation of HO-1 [Martin et al, 2004]. Previously, Lifshitz et al demonstrated that the dendritic cells (DCs) are direct targets of EPO, to initiate the immune response through the overexpression of human EPO in transgenic mice in in vivo experiments and validate a higher expression of EPO-R mRNA from bone marrowderived DCs (BM-DCs) [Lifshitz et al, 2009]. Recent reports indicate that EPO exerts its cytoprotective effects in cardiac ischemia-reperfusion injury by inducing HO-1 expression [Burger et al, 2009] www.intechopen.com…”