Abstract
Objective:Thalassemia is one of the genetic diseases that cause anemia and ineffective erythropoiesis. Increased levels of several inflammatory cytokines have been reported in β-thalassemia and might contribute to ineffective erythropoiesis. However, the mechanism by which tumor necrosis factor-alpha (TNF-α) is involved in ineffective erythropoiesis in thalassemic patients remains unclear. The objective of this study is to investigate the effect of TNF-α on the erythropoietin (EPO) and erythropoietin receptor (EPOR) expression involved in proliferation of β-thalassemia/hemoglobin (Hb) E erythroid progenitor cells compared with cells from healthy subjects.Materials and Methods:CD34-positive cells were isolated from heparinized blood by using the EasySep® CD34 selection kit. Cells were then cultured with suitable culture medium in various concentrations of EPO for 14 days. The effect of TNF-α on percent cell viability was analyzed by trypan blue staining. In addition, the percentage of apoptosis and levels of EPOR protein were measured by flow cytometry.Results:Upon EPO treatment, a higher cell number was observed for erythroid progenitor cells from both healthy participants and β-thalassemia/Hb E patients. However, a reduction of apoptosis was found in EPO-treated cells especially for β-thalassemia/Hb E patients. Interestingly, TNF-α caused higher levels of cell apoptosis and lower levels of EPOR protein in thalassemic erythroid progenitor cells.Conclusion:TNF-α caused a reduction in the level of EPOR protein and EPO-induced erythroid progenitor cell proliferation. It is possible that TNF-α could be involved in the mechanism of ineffective erythropoiesis in β-thalassemia/Hb E patients.
Highlights
Upon EPO treatment, a higher cell number was observed for erythroid progenitor cells from both healthy participants and β-thalassemia/Hb E patients
A reduction of apoptosis was found in EPO-treated cells especially for β-thalassemia/ Hb E patients
TNF-α caused a reduction in the level of erythropoietin receptor (EPOR) protein and EPO-induced erythroid progenitor cell proliferation
Summary
The major pathophysiological features include ineffective erythropoiesis and anemia. In terms of ineffective erythropoiesis, the mechanism includes increased intramedullary erythroid death and arrested proliferation of erythroid progenitors, which plays an important role in β-thalassemia [1]. Erythropoietin (EPO) is a glycoprotein hormone required for the survival, proliferation, and differentiation of committed erythroid progenitor cells. The erythropoietin receptor (EPOR) belongs to the cytokine receptor superfamily, which includes receptors for other hematopoietic growth factors such as interleukins, colony-stimulating factors, and growth hormone. EPO binds to EPOR and causes the signaling pathways to control survival and proliferation of erythroid cells [3]. Survival signaling by EPOR is essential for erythropoiesis and for its acceleration in hypoxic stress. Several apparently redundant EPOR survival pathways were identified in vitro, raising the possibility of their functional specialization in vivo [4]
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