Abstract
Resistance to erythropoietin (EPO) affects a significant number of anaemic patients with end-stage renal disease. Previous reports suggest that inflammation is one of the major independent predictors of EPO resistance, and the effects of EPO treatment on inflammatory mediators are not well established. The aim of this study was to investigate EPO-induced modification to gene expression in primary cultured leucocytes. Microarray experiments were performed on primed ex vivo peripheral blood mononuclear cells (PBMCs) and treated with human EPO-α. Data suggested that EPO-α modulated genes involved in cell movement and interaction in primed PBMCs. Of note, EPO-α exerts anti-inflammatory effects inhibiting the expression of pro-inflammatory cytokine IL-8 and its receptor CXCR2; by contrast, EPO-α increases expression of genes relating to promotion of inflammation encoding for IL-1β and CCL8, and induces de novo synthesis of IL-1α, CXCL1 and CXCL5 in primed cells. The reduction in MAPK p38-α activity is involved in modulating both IL-1β and IL-8 expression. Unlike the induction of MAPK, Erk1/2 activity leads to upregulation of IL-1β, but does not affect IL-8 expression and release. Furthermore, EPO-α treatment of primed cells induces the activation of caspase-1 upstream higher secretion of IL-1β, and this process is not dependent on caspase-8 activation. In conclusion, our findings highlight new potential molecules involved in EPO resistance and confirm the anti-inflammatory role for EPO, but also suggest a plausible in vivo scenario in which the positive correlation found between EPO resistance and elevated levels of some pro-inflammatory mediators is due to treatment with EPO itself.
Highlights
Anaemia is an inevitable condition that develops early in the course of chronic kidney disease (CKD) and increases in frequency while the glomerular filtration rate further declines [1]
It has been reported that anaemia in CKD is associated with upregulation of TNF-a, along with increased levels of this pro-inflammatory cytokine in patients treated with erythropoiesis-stimulating agents (ESAs) [19]. These findings suggest that the effects of EPO treatment on inflammatory mediators are strictly dependent on the phase and intensity of the inflammatory condition present during drug administration
The alteration of gene expression is mainly implicated in regulation of cellular development, though in peripheral blood mononuclear cells (PBMCs) dynamic processes, such as cell movement and cell-to-cell interaction
Summary
Anaemia is an inevitable condition that develops early in the course of chronic kidney disease (CKD) and increases in frequency while the glomerular filtration rate further declines [1]. Pro-inflammatory cytokines simultaneously affect erythropoiesis at several levels, and manifest their effects as ‘inflammation anaemia’ and hyporesponsiveness to EPO treatment in patients with CKD [8]. Pro-inflammatory cytokines can, cause EPO resistance, inhibiting the in vitro growth of erythroid progenitors [9,10,11] and interfering with iron homeostasis. TNF-a and IL-1 can damage the erythrocyte membranes and stimulate erythrocyte phagocytosis [12,13]. All these processes promote the intracellular accumulation of iron by reducing its bioavailability, reduce the production of endogenous EPO as well as the bone marrow response to the erythropoietic stimulus, and end by making and keeping patients anaemic [14]
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