The Polymorphonuclear Leukocyte – A New Target for Erythropoietin

Sela, Shifra; Shurtz-Swirski, Revital; Sharon, Ronit; Manaster, J.; Chezar, Judith; Школьник, Г. С.; Shapiro, Galina; Shasha, Shaul M.; Merchav, Shoshana; Kristal, Batya

doi:10.1159/000045991

Cited by 52 publications

(36 citation statements)

References 27 publications

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“…The detection of EPO-Rs in cells other than erythroid progenitors, such as polymorphonuclear leukocytes, megakaryocytes, endothelial, myocardial and neural cells (Anagnostou et al, 1994;Brines and Cerami, 2005;Buemi et al, 2003;Fraser et al, 1989;Jaquet et al, 2002;Sela et al, 2001) showed that besides its role in erythropoiesis, EPO has additional biological functions. It should be noted that alongside the beneficial effects of EPO, a concern that EPO treatment for anemia might adversely affect the prognosis in certain cases of solid tumor cancers (Aapro et al, 2008;Henke et al, 2006;Longmore, 2007) has been raised.…”

Section: Introductionmentioning

confidence: 99%

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

Lifshitz

Prutchi-Sagiv

Avneon

et al. 2009

Molecular Immunology

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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.

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Section: Introductionmentioning

confidence: 99%

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

Lifshitz

Prutchi-Sagiv

Avneon

et al. 2009

Molecular Immunology

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“…Cloning of the Epo gene has led to the introduction of recombinant human Epo (rHuEpo) into clinical practice as a treatment for various anemias, including anemia related to chronic kidney disease and certain forms of cancer [1, 2]. Detection of the target receptor for Epo (EpoR) in cells other than erythroid progenitors, such as polymorphonuclear leukocytes, megakaryocytes, endothelial, myocardial and neural cells [3][4][5][6][7], suggests that Epo has other biological functions beyond erythropoiesis, and may have further potential therapeutic applications. These effects include improvement in congestive heart failure [8,9] and neuroprotection [10][11][12][13][14][15][16][17].…”

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confidence: 99%

Erythropoietin enhances immune responses in mice

et al. 2007

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Erythropoietin (Epo) is the main erythropoietic hormone. Recombinant human Epo (rHuEpo) is thus used in clinical practice for the treatment of anemia. Accumulating data reveals that Epo exerts pleiotropic activities. We have previously shown an antineoplastic activity of Epo in murine multiple myeloma (MM) models, and in MM patients. Our findings that this anti-neoplastic effect operates via CD8 + T lymphocytes led us to hypothesize that Epo possesses a wider range of immunomodulatory functions. Here we demonstrate the effect of Epo on B lymphocyte responses, focusing on three experimental models: (i) tumor-bearing mice, (5T2 MM mouse); (ii) antigen-injected healthy mice; and (iii) antigen-injected transgenic mice (tg6), overexpressing human Epo. In the MM model, despite bone marrow dysfunction, Epo-treated mice retained higher levels of endogenous polyclonal immunoglobulins, compared to their untreated controls. In both Epo-treated wild type and tg6 mice, Epo effect was manifested in the higher levels of splenocyte proliferative response induced in vitro by lipopolysaccharide. Furthermore, these mice had increased in vivo production of anti-dinitrophenyl (DNP) antibodies following immunization with DNP-keyhole limpet hemocyanin. Epo-treated mice showed an enhanced immune response also to the clinically relevant hepatitis B surface antigen. These findings suggest a potential novel use of rHuEpo as an immunomodulator.See accompanying commentary: http://dx.doi. org/10.1002/eji.200737401 Introduction Erythropoietin (Epo), produced mainly in the adult kidney, is the major growth regulator of the erythroid cell lineage. Cloning of the Epo gene has led to the introduction of recombinant human Epo (rHuEpo) into clinical practice as a treatment for various anemias, including anemia related to chronic kidney disease and certain forms of cancer [1, 2]. Detection of the target receptor for Epo (EpoR) in cells other than erythroid progenitors, such as polymorphonuclear leukocytes, megakaryocytes, endothelial, myocardial and neural cells [3][4][5][6][7], suggests that Epo has other biological functions beyond erythropoiesis, and may have further potential therapeutic applications. These effects include improvement in congestive heart failure [8,9] and neuroprotection [10][11][12][13][14][15][16][17].* These authors contributed equally to this study. The idea that rHuEpo may have an important effect on the immune system, including both cellular and humoral type responses, derives from several lines of data, as recently reviewed [18]. For instance, clinical observations revealed that treatment with rHuEpo was associated with enhanced antibody production in hemodialysis patients, demonstrated for T cell-dependent antigens, such as tetanus toxoid and hepatitis B [19][20][21][22] as well as for the T cell-independent pneumococcal polysaccharide antigen [20]. Others have demonstrated enhancement of basal and mitogen-stimulated immunoglobulin production by cultured peripheral mononuclear cells (MNC) of dialysis patients treated ...

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“…The upregulation of ICAM-1 in tg6 mice emphasizes this point and could also help explain the previous negative outcome observed in these mice after MCAO. In the absence of injury, however, because leukocytes express functional Epo receptors (38), Epo may directly interact with and reduce the number of leukocytes and slow the inflammatory response as a whole (39). Although a detrimental effect of high Epo levels on the vasculature cannot be ruled out, clinically Epo is a very well studied and frequently used compound, and all current evidence suggests that this is unlikely to be the case (for a review see Ref.…”

Section: Discussionmentioning

confidence: 99%