Erythropoietin receptor is detectable on peripheral blood lymphocytes and its expression increases in activated T lymphocytes

Lisowska, Katarzyna A.; Bryl, Ewa; Witkowski, Jacek M.

doi:10.3324/haematol.2010.038414

Cited by 12 publications

(12 citation statements)

References 6 publications

(7 reference statements)

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“…Our results extend previously published work by others documenting EPO-R on human T cells 20,21 by uniquely revealing that EPO exhibits immunosuppressive properties. EPO inhibits T-cell proliferation, expansion, and IFN-g production without inducing T-cell death or altering Treg generation (Figures 1-3).…”

Section: Discussionsupporting

confidence: 80%

Immunosuppressive Effects of Erythropoietin on Human Alloreactive T Cells

Cravedi¹,

Manrique²,

Hanlon

et al. 2014

Journal of the American Society of Nephrology

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Correction of anemia with erythropoietin (EPO) is associated with improved kidney transplant outcomes. Emerging evidence, predominantly from animal models, indicates that these observations may be erythropoiesis-independent and that EPO exhibits immunosuppressive properties. We examined the effects of EPO on human T-cell alloimmunity by first documenting that CD4 + and CD8 + T cells express EPO receptor (EPO-R) on their surfaces. In mixed lymphocyte reactions, EPO induced a dose-dependent decrease in allogeneic CD4 + T-cell proliferation (EPO 1000 U/ml: 44.6%622.9% of vehicle, P,0.05; 2000 U/ml: 11.1%64% of vehicle, P,0.001) without inducing cell death. The effects required signals transmitted directly through the EPO-R expressed on T cells, resulting in diminished Th1 differentiation without effects on regulatory T-cell induction. Mechanistic studies revealed that EPO prevented IL-2-induced proliferation by uncoupling IL-2 receptor signaling, inhibiting phosphorylation of the intracellular intermediaries AKT and extracellular signal-regulated kinase that are known to mediate T-cell expansion. EPO treatment reduced expansion of human naïve CD4 + T cells after adoptive transfer into NOD scid gc null mouse recipients, verifying the effects in vivo. Although activated T cells expressed CD131, an alternative EPO receptor, addition of a specific CD131 agonist peptide, ARA290, did not alter T-cell proliferation or cytokine production. Our findings link EPO-R signaling on T cells to inhibition of T-cell immunity, providing one mechanism that could explain the observed protective effects of EPO in kidney transplant recipients. The anemia that commonly occurs in kidney transplant recipients has been hypothesized to contribute to chronic allograft injury, in part by limiting oxygen delivery to the tubulointersitium and as a consequence, enabling fibrogenesis. 1 In support of a link between anemia and kidney allograft injury, results of a 2012 randomized controlled study of erythropoietin (EPO) therapy after transplantation showed that targeting hemoglobin values to a normal range of $13 g/dl slowed progression of chronic allograft nephropathy and prolonged graft survival compared with partial correction of anemia. 2 Although the above-cited clinical study and selected studies in rodents indicate correlations between EPO-induced increases in hematocrit and reduced tubulointerstitial damage as well as preserved renal tubular cells and improved kidney function, 3 direct evidence linking EPO-induced erythropoiesis to better transplant outcomes is lacking. In fact, experiments performed in a fully mismatched rat kidney transplant model showed that EPO, but not the correction of anemia by blood transusion, limits chronic allograft injury, 4,5 supporting the conclusion that the transplant-protective effects of EPO do not require an EPO-induced increase in hematocrit. Among potential alternative mechanisms, emerging evidence from animal models suggests that

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Section: Discussionsupporting

confidence: 80%

Immunosuppressive Effects of Erythropoietin on Human Alloreactive T Cells

Cravedi¹,

Manrique²,

Hanlon

et al. 2014

Journal of the American Society of Nephrology

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“…It has been shown previously that resting T cells express about 100 copies of EpoR per cell which increases 10 fold upon T cell activation, thus reaching the expression levels typical for erythroid precursor cells [3]. These observations suggest an important role for Epo in regulating adaptive immune responses.…”

Section: Introductionmentioning

confidence: 91%

“…The major role of Epo consists in up-regulating erythropoiesis which occurs primarily via binding to its cognate monomeric membrane receptor which is activated by ligand-induced homodimerization [2]. Epo is a pleiotropic cytokine, and its receptors were shown to be expressed on nonhematopoietic cells, such as neuronal cells, endothelial cells, interstitial Leydig cells, megakaryocytes, monocytes, macrophages, and lymphocytes [3]. Interestingly, Epo receptors (EpoRs) expressed in nonhematopoietic cells pre-exist in a dimeric form that consists of an Epo alpha-chain and common beta-chain (bcR) that is shared with receptors for IL-3, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-SCF) [4].…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin exerts direct immunomodulatory effects on the cytokine production by activated human T-lymphocytes

Тодосенко

Shmarov

Малащенко

et al. 2016

International Immunopharmacology

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“…Although the blood volume at each collection is small (1.5 ml ϭ 1% of the total blood volume), the total volume over the 7 days is more substantial (22.5 ml ϭ 15% of the total blood volume). Hematopoietic growth factors that stimulate the bone marrow are known to be not cell type specific (12). Indeed, with this relatively small amount of blood removed over a long period, it is unlikely that the blood loss significantly impacts PMN transit times.…”

Section: Discussionmentioning

confidence: 99%

“…The catheter was flushed with 50 -100 l of heparin (1,000 U/ml), closed with a plastic luer-lok cap and held in place with Beiersdorf Leukoplast adhesive tape. Blood samples (1.5 ml at a time) were obtained just before the ninth instillation (baseline) and at 4,8,12,16,20,24,30,36,48,72,96,120,144, and 168 h after the ninth instillation. No sedative agents were required to collect blood from the indwelling 20G catheter, and towel restraint provided warmth and comfort to the rabbit.…”

Section: Methodsmentioning

confidence: 99%

Novel properties of statins: suppression of the systemic and bone marrow responses induced by exposure to ambient particulate matter (PM₁₀) air pollution

Miyata

Bai

Vincent

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Exposure to ambient particulate matter (PM10) elicits systemic inflammatory responses that include the stimulation of bone marrow and progression of atherosclerosis. The present study was designed to assess the effect of repeated exposure of PM10on the turnover and release of polymorphonuclear leukocytes (PMNs) from the bone marrow into the circulation and the effect of lovastatin on the PM10-induced bone marrow stimulation. Rabbits exposed to PM10three times a week for 3 wk, were given a bolus of 5′-bromo-2′-deoxyuridine to label dividing cells in the marrow to calculate the transit time of PMNs in the mitotic or postmitotic pool. PM10exposure accelerated the turnover of PMNs by shortening their transit time through the marrow (64.8 ± 1.9 h vs. 34.3 ± 7.4 h, P < 0.001, control vs. PM10). This was predominantly due to a rapid transit of PMNs through the postmitotic pool (47.9 ± 0.7 h vs. 21.3 ± 4.3 h, P < 0.001, control vs. PM10) but not through the mitotic pool. Lovastatin delayed the transit time of postmitotic PMNs (38.2 ± 0.5 h, P < 0.001 vs. PM10) and shifted the postmitotic PMN release peak from 30 h to 48 h. PM10exposure induced the prolonged retention of newly released PMNs in the lung, which was reduced by lovastatin ( P < 0.01). PM10exposure increased plasma interleukin-6 levels with significant reduction by lovastatin ( P < 0.01). We conclude that lovastatin downregulates the PM10-induced overactive bone marrow by attenuating PM10-induced systemic inflammatory responses.

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Erythropoietin receptor is detectable on peripheral blood lymphocytes and its expression increases in activated T lymphocytes

Cited by 12 publications

References 6 publications

Immunosuppressive Effects of Erythropoietin on Human Alloreactive T Cells

Immunosuppressive Effects of Erythropoietin on Human Alloreactive T Cells

Erythropoietin exerts direct immunomodulatory effects on the cytokine production by activated human T-lymphocytes

Novel properties of statins: suppression of the systemic and bone marrow responses induced by exposure to ambient particulate matter (PM₁₀) air pollution

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Erythropoietin receptor is detectable on peripheral blood lymphocytes and its expression increases in activated T lymphocytes

Cited by 12 publications

References 6 publications

Immunosuppressive Effects of Erythropoietin on Human Alloreactive T Cells

Immunosuppressive Effects of Erythropoietin on Human Alloreactive T Cells

Erythropoietin exerts direct immunomodulatory effects on the cytokine production by activated human T-lymphocytes

Novel properties of statins: suppression of the systemic and bone marrow responses induced by exposure to ambient particulate matter (PM10) air pollution

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Resources

About

Novel properties of statins: suppression of the systemic and bone marrow responses induced by exposure to ambient particulate matter (PM₁₀) air pollution