Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti–tumor necrosis factor-α antibody therapy

Papadaki, Helen Α.; Kritikos, H; Valatas, Vassilis; Boumpas, Dimitrios T.; Eliopoulos, George D.

doi:10.1182/blood-2002-01-0136

Cited by 243 publications

(181 citation statements)

References 41 publications

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“…Although we could not examine the patient's marrow, the pathogenesis of the PK-deficient anemia may be partly explained by enhanced clearance of apoptotic erythroid precursors in the spleen. Erythroid apoptosis has been observed in ␤-thalassemia major [17], Diamond-Blackfan anemia [18], myelodysplastic syndromes [19], folate deficiency [20], sideroblastic anemia [21], or anemia associated with rheumatoid arthritis [22]. It remains to be elucidated how and where the apoptotic erythroid cells are eliminated in each case.…”

Section: Discussionmentioning

confidence: 99%

Ineffective erythropoiesis in the spleen of a patient with pyruvate kinase deficiency

et al. 2003

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In this study, possible adverse effects of pyruvate kinase (PK) deficiency on the maturation of erythroid progenitors were investigated. A 4-year-old Japanese girl with severe PK deficiency underwent splenectomy to reduce her need for blood transfusions. The spleen was examined a histologically, and the hematopoietic progenitors in the spleen were assayed to evaluate the extramedullary hematopoiesis of this PK-deficient subject. The number of hematopoietic progenitors including CFU-GM, BFU-E and CFU-GEMM in the spleen of the PK-deficient patient was much higher than those found in control spleens, indicating enhanced extramedullary hematopoiesis. TUNEL assay demonstrated apoptotic cells in the splenic red pulp of the PK-deficient patient. The expression of 7A6 antigen was detected in cells isolated from spleen and in cells cultured in vitro, but only in those cells that were positive for glycophorin A. These results provide evidence that the metabolic disturbances in PK deficiency affect not only the survival of red cells but also the maturation of erythroid progenitors, which results in premature cell death, i.e., apoptosis. Am. J. Hematol. 74:68-72, 2003.

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Section: Discussionmentioning

confidence: 99%

Ineffective erythropoiesis in the spleen of a patient with pyruvate kinase deficiency

et al. 2003

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“…Indeed, patients suffering from cancer and chronic inflammation are often anemic [7]. Moreover, in vitro and in vivo studies have led to the conclusion that TNF inhibits hematopoietic progenitors from undergoing erythroid differentiation [8][9][10][11][12][13][14][15]. Anti-TNF treatment is effectively used for the treatment of chronic inflammatory diseases, but leads to increased risk of infection [16,17].…”

Section: Introductionmentioning

confidence: 99%

Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression

Grigorakaki

Morceau

Chateauvieux

et al. 2011

Biochemical Pharmacology

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Many physiological perturbations can cause anemia. In cancer patients, activation of the immune system leads to the production of proinflammatory cytokines including tumor necrosis factor alpha (TNF), that have been shown to inhibit red-cell production via poorly understood mechanisms. Treatment of anemia by human recombinant erythropoietin (EPO) is strongly suspected to induce tumor growth.This study focuses on the mechanisms involved in TNF-mediated inhibition of erythropoiesis. CD34 + hematopoietic stem/progenitor cells (HSPC) were isolated from human cord blood. Erythropoiesis was achieved in vitro by stimulating cells with EPO. We show that TNF clearly affected erythroid development, as assessed by May-Grünwald/Giemsa staining, flow cytometry analysis and fluorescent microscopy. The amount of hemoglobinproducing cells as well as the expression of GATA-1 target erythro-specific genes (EPO receptor, glycophorin A and globins) was found decreased after TNF treatment of HSPC. In correlation, TNF induced the expression of the transcription factors GATA-2 and PU.1, described as inhibitors of erythropoiesis. In this regard, TNF promoted the formation of the GATA-1/PU.1 complex that has been reported to block the transcriptional activity of GATA-1. Our results clearly demonstrate that TNF prevents EPO-mediated erythropoiesis of HSPC as an early event, by directly affecting erythroid cell development.Keywords: anemia; inflammation; TNF; GATA-1; GATA-2; PU.1Page 3 of 38 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 -3 - IntroductionThe majority of tumors are largely infiltrated by inflammatory cells, such as myelomonocytes and macrophages [1]. In response to the inflammatory environment, these cells produce inflammatory mediators including chemokines and cytokines. These mediators are tightly associated with cancer progression in combination with genetic alterations [2]. One of them, the Tumor Necrosis Factor alpha (TNF), is widely found in the inflammationassociated cancer microenvironment [3][4][5][6]. Interestingly, because TNF is commonly present in cancer and inflammatory diseases, it has been implicated in cancer-and inflammationrelated anemia. Indeed, patients suffering from cancer and chronic inflammation are often anemic [7]. Moreover, in vitro and in vivo studies have led to the conclusion that TNF inhibits hematopoietic progenitors from undergoing erythroid differentiation [8][9][10][11][12][13][14][15]. Anti-TNF treatment is effectively used for the treatment of chronic inflammatory diseases, but leads to increased risk of infection [16,17]. Despite the beneficial effects of anti-TNF, this treatment may promote different types of cancers [18,19].Several events may trigger anemia, including iron deficiency, hemolysis and hemorrhage. In non-hematopo...

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“…Moreover we suggested a role for p38 in the inhibition of erythroid differentiation by TNFα, in correlation with a reversal of important erythroid transcription factors [78]. Miwatashi and colleagues already used a novel p38 presenting anemic complications [11,80].…”

Section: Deregulation Of Erythropoiesis By Tnfα α α α In Inflammationmentioning

confidence: 85%

“…TNFα was also shown to have a direct inhibitory effect on Epo-induced generation of GPA positive cells from CD34+ progenitors, leading to the suppression of erythropoiesis and the reduction of the proliferation capacity of GPA positive cells [61]. Interestingly, TNFα is also believed to play a critical role in many forms of cancer [9,62] and inflammation related anemia [11]. Indeed anemia is considered as a common symptom induced by inflammation and cancer pathologies.…”

Section: Deregulation Of Erythropoiesis By Tnfα α α α In Inflammationmentioning

confidence: 99%

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Linking anemia to inflammation and cancer: The crucial role of TNFα

Buck

Morceau

Grigorakaki

et al. 2009

Biochemical Pharmacology

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Erythropoiesis is considered as a multistep and tightly regulated process under the control of a series of cytokines including erythropoietin (Epo). Epo activates specific signaling pathways and leads to activation of key transcription factors such as GATA-1, in order to ensure erythroid differentiation. Deregulation leads to a decreased number of red blood cells, a hemoglobin deficiency, thus a limited oxygen-carrying capacity in the blood. Anemia represents a frequent complication in various diseases such as cancer or inflammatory diseases. It reduces both quality of life and prognosis in patients. Tumor necrosis factor alpha (TNFα) was described to be involved in the pathogenesis of inflammation and cancer related anemia. Blood transfusions and erythroid stimulating agents (ESAs) including human recombinant Epo (rhuEpo) are currently used as efficient treatments. Moreover, the recently described conflicting effects of ESAs in distinct studies require further investigations on the molecular mechanisms involved in TNFα-caused anemia. The present study aims to evaluate the current knowledge and the importance of the effect of the proinflammatory cytokine TNFα on erythropoiesis in inflammatory and malignant conditions.

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Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti–tumor necrosis factor-α antibody therapy

Cited by 243 publications

References 41 publications

Ineffective erythropoiesis in the spleen of a patient with pyruvate kinase deficiency

Ineffective erythropoiesis in the spleen of a patient with pyruvate kinase deficiency

Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression

Linking anemia to inflammation and cancer: The crucial role of TNFα

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