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1.
Ann Allergy Asthma Immunol ; 108(1): 34-38, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22192963

RESUMO

BACKGROUND: The spleen is a key organ within the immune system. Its removal is known to bring about adverse effects such as an increased susceptibility to overwhelming infection. Few reports have suggested that the spleen may play a role in controlling eosinophilic responses, mostly based on animal models. OBJECTIVES: To examine whether the human spleen impacts eosinophil numbers in the blood. METHODS: We have retrospectively analyzed eosinophil counts and medical records of 29 patients who had undergone splenectomy between 2000 and 2010. Statistical comparison was performed between post-splenectomy blood counts and both pre-splenectomy and control values. Data regarding the clinical settings around hypereosinophilia events were obtained from patient charts. RESULTS: An increased rate of eosinophilia was observed after splenectomy as compared with normal individuals. Furthermore, a considerable proportion of patients who had undergone splenectomies (8/29) presented peak eosinophil numbers exceeding 1,000/mm(3), reaching a maximum of 3,070/mm(3). These values were mostly encountered perioperatively or during episodes of acute infection. CONCLUSIONS: Our data indicate that impaired control of eosinophilic responses is a long-term post-splenectomy effect and is evident in the context of acute stress. We suggest that the spleen plays a significant role in controlling eosinophil levels and that these cells may mediate some of the harmful consequences observed after removal of the spleen.


Assuntos
Eosinofilia/etiologia , Eosinófilos/citologia , Esplenectomia/efeitos adversos , Adulto , Eosinófilos/imunologia , Feminino , Humanos , Sistema Imunitário , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Baço/imunologia
2.
Haematologica ; 95(11): 1823-31, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20595096

RESUMO

BACKGROUND: Our original demonstration of immunomodulatory effects of erythropoietin in multiple myeloma led us to the search for the cells in the immune system that are direct targets for erythropoietin. The finding that lymphocytes do not express erythropoietin receptors led to the hypothesis that other cells act as direct targets and thus mediate the effects of erythropoietin. The finding that erythropoietin has effects on dendritic cells thus led to the question of whether macrophages act as target cells for erythropoietin. DESIGN AND METHODS: The effects of erythropoietin on macrophages were investigated both in-vivo and in-vitro. The in-vivo studies were performed on splenic macrophages and inflammatory peritoneal macrophages, comparing recombinant human erythropoietin-treated and untreated mice, as well as transgenic mice over-expressing human erythropoietin (tg6) and their control wild-type counterparts. The in-vitro effects of erythropoietin on macrophage surface markers and function were investigated in murine bone marrow-derived macrophages treated with recombinant human erythropoietin. RESULTS: Erythropoietin was found to have effects on macrophages in both the in-vivo and in-vitro experiments. In-vivo treatment led to increased numbers of splenic macrophages, and of the splenic macrophages expressing CD11b, CD80 and major histocompatibility complex class II. The peritoneal inflammatory macrophages obtained from erythropoietin-treated mice displayed increased expression of F4/80, CD11b, CD80 and major histocompatibility complex class II, and augmented phagocytic activity. The macrophages derived in-vitro from bone marrow cells expressed erythropoietin receptor transcripts, and in-vitro stimulation with erythropoietin activated multiple signaling pathways, including signal transducer and activator of transcription (STAT)1 and 5, mitogen-activated protein kinase, phosphatidylinositol 3-kinase and nuclear factor kappa B. In-vitro erythropoietin treatment of these cells up-regulated their surface expression of CD11b, F4/80 and CD80, enhanced their phagocytic activity and nitric oxide secretion, and also led to augmented interleukin 12 secretion and decreased interleukin 10 secretion in response to lipopolysaccharide. CONCLUSIONS: Our results show that macrophages are direct targets of erythropoietin and that erythropoietin treatment enhances the pro-inflammatory activity and function of these cells. These findings point to a multifunctional role of erythropoietin and its potential clinical applications as an immunomodulating agent.


Assuntos
Células da Medula Óssea/metabolismo , Eritropoetina/farmacologia , Fatores Imunológicos/farmacologia , Macrófagos/metabolismo , Fagocitose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Antígenos de Diferenciação/biossíntese , Antígenos de Diferenciação/genética , Antígeno B7-1/biossíntese , Antígeno B7-1/genética , Células da Medula Óssea/citologia , Antígeno CD11b/biossíntese , Antígeno CD11b/genética , Células Cultivadas , Eritropoetina/genética , Eritropoetina/metabolismo , Feminino , Antígenos de Histocompatibilidade Classe II/biossíntese , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Fatores Imunológicos/genética , Fatores Imunológicos/metabolismo , Interleucina-10/biossíntese , Interleucina-10/genética , Interleucina-12/biossíntese , Interleucina-12/genética , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Camundongos , Camundongos Transgênicos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Fagocitose/fisiologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Recombinantes , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
3.
J Endocrinol ; 205(1): 87-95, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20061512

RESUMO

Erythropoietin (EPO) regulates proliferation and differentiation of erythroid precursor cells into erythrocytes. The last decade has revealed non-renal sites of EPO production and extrahematopoietic expression of the EPO receptor, thus suggesting that EPO has pleiotropic functions. Here, we addressed the interplay between EPO/glucose metabolism/body weight by employing a panel of relevant experimental murine models. The models focused on situations of increased EPO levels, including EPO-injected C57BL/6 and BALB/c mice, as well as transgenic mice (tg6) constitutively overexpressing human EPO, thus exposed to constantly high EPO serum levels. As experimental models for diabetes and obesity, we employed protein Tyr phosphatase 1B (PTP1B) knockout mice associated with resistance to diabetes (PTP1B(-/-)), and ob/ob mice susceptible to diabetes and obesity. The data presented herein demonstrate EPO-mediated decrease in blood glucose levels in all mice models tested. Moreover, in the ob/ob mice, we observed EPO-mediated attenuation of body weight gain and reduction of hemoglobin A1c. Taken together, our data bear significant clinical implications of EPO treatment in the management of a wide range of metabolic diseases, thus adding an important novel therapeutic potential to this pleiotropic hormone.


Assuntos
Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Índice de Massa Corporal , Eritropoetina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Eritropoetina/metabolismo , Feminino , Hemoglobinas Glicadas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Modelos Animais , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo
5.
Leuk Res ; 33(10): 1430-2, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19376577

RESUMO

We have previously shown that erythropoietin (EPO) potentiates the immune response. Analysis of various possible cellular mediators was performed on EPO-injected mice and transgenic mice overexpressing human EPO (tg6). Here we present our studies on neutrophils, peritoneal (casein induced), and from the peripheral blood, spleen and bone marrow. Neutrophil counts were elevated in peripheral blood and spleens of the tg6 mice, yet, no other EPO-associated effects were detected in the count and function of the different neutrophil populations. Hence, neutrophils are probably not mediators of the EPO immunological effects, although their counts may be affected by extreme EPO levels.


Assuntos
Eritropoetina/farmacologia , Eritropoetina/uso terapêutico , Neutrófilos/fisiologia , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/fisiologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Epoetina alfa , Eritropoetina/genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neutrófilos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes
6.
Mol Immunol ; 46(4): 713-21, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19027957

RESUMO

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.


Assuntos
Células Dendríticas/imunologia , Eritropoetina/metabolismo , Receptores da Eritropoetina/metabolismo , Transdução de Sinais/imunologia , Animais , Antígeno B7-1/imunologia , Antígeno B7-1/metabolismo , Antígeno B7-2/imunologia , Antígeno B7-2/metabolismo , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/metabolismo , Eritropoetina/imunologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosforilação/imunologia , Receptores da Eritropoetina/imunologia , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/imunologia , Fator de Transcrição STAT5/metabolismo , Baço/imunologia , Baço/metabolismo
7.
Exp Hematol ; 36(12): 1682-90, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18922618

RESUMO

OBJECTIVE: Modulatory effects of erythropoietin (EPO) on the cellular and humoral compartments of the immune system have been described; however, the mechanism of action by which EPO affects the lymphocyte number and functions has yet to be elucidated. Because no EPO receptors (EPO-R) could be detected on lymphocytes, we searched for cells that might express the EPO-R and thereby mediate these immunomodulatory effects. We thus focused on dendritic cells (DCs), the most potent antigen-presenting and T-cell-priming cells, as possible mediators of the immunomodulatory actions of EPO. MATERIALS AND METHODS: We examined the in vitro effects of EPO on human DCs. Expression of EPO-R, expression of costimulatory molecules, antigen uptake, secretion of cytokines, and DC maturation were investigated. RESULTS: We demonstrate that the EPO-R is expressed in human DCs and that EPO directly affects their phenotype and function. When applied in vitro, EPO increased the percentage of peripheral blood DCs and monocyte-derived DCs (MoDCs) expressing the costimulatory molecules CD80 and CD86. EPO treatment of MoDCs was also associated with an increase in surface expression of CD80 and CD86 as well as that of HLA-DR. EPO enhanced MoDC function, as manifested in increased antigen uptake and secretion of interleukin 12. When applied to immature MoDCs, EPO in itself induced their maturation. CONCLUSION: Our finding that DCs are directly affected by EPO renders them as potential candidates that mediate the immunomodulatory actions of EPO.


Assuntos
Células Dendríticas/imunologia , Eritropoetina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Monócitos/imunologia , Receptores da Eritropoetina/imunologia , Antígeno B7-1/imunologia , Antígeno B7-2/imunologia , Células Dendríticas/citologia , Epoetina alfa , Eritropoetina/imunologia , Regulação da Expressão Gênica/imunologia , Antígenos HLA-DR/imunologia , Hematínicos/imunologia , Hematínicos/farmacologia , Humanos , Fatores Imunológicos/imunologia , Interleucina-12/imunologia , Monócitos/citologia , Receptores da Eritropoetina/agonistas , Proteínas Recombinantes , Linfócitos T/citologia , Linfócitos T/imunologia
8.
Eur J Immunol ; 37(6): 1584-93, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17458859

RESUMO

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 anti-neoplastic 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.


Assuntos
Adjuvantes Imunológicos/farmacologia , Formação de Anticorpos/efeitos dos fármacos , Eritropoetina/farmacologia , Adjuvantes Imunológicos/genética , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Formação de Anticorpos/imunologia , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Complexo CD3/imunologia , Proliferação de Células/efeitos dos fármacos , Eritropoetina/genética , Eritropoetina/uso terapêutico , Feminino , Hemocianinas/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Humanos , Imunoglobulina G/sangue , Cadeias gama de Imunoglobulina/sangue , Cadeias kappa de Imunoglobulina/sangue , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mieloma Múltiplo/sangue , Mieloma Múltiplo/tratamento farmacológico , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Análise de Sobrevida , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Vacinação
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