title: Effect of erythropoietin on primed leucocyte expression profile.
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.
authors.affiliation: Department of Psychological, Humanistic and Territorial Sciences, University 'G. D'Annunzio', Chieti, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Pesce
authors.affiliation: Department of Medicine and Science of Aging, University 'G. D'Annunzio', Chieti, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Felaco
authors.affiliation: Department of Medicine and Science of Aging, University 'G. D'Annunzio', Chieti, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Franceschelli
authors.affiliation: Department of Medicine and Science of Aging, University 'G. D'Annunzio', Chieti, Italy l.speranza@unich.it.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Speranza
authors.affiliation: Department of Medicine and Science of Aging, University 'G. D'Annunzio', Chieti, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Grilli
authors.affiliation: Department of Medicine and Science of Aging, University 'G. D'Annunzio', Chieti, Italy.
authors.forename: Maria Anna
authors.initials: MA
authors.lastname: De Lutiis
authors.affiliation: Department of Medicine and Science of Aging, University 'G. D'Annunzio', Chieti, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Ferrone
authors.affiliation: Department of Medicine and Science of Aging, University 'G. D'Annunzio', Chieti, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Sirolli
authors.affiliation: Department of Medicine and Science of Aging, University 'G. D'Annunzio', Chieti, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Bonomini
authors.affiliation: Department of Medicine and Science of Aging, University 'G. D'Annunzio', Chieti, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Felaco
authors.affiliation: Department of Medicine and Science of Aging, University 'G. D'Annunzio', Chieti, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Patruno
mesh_terms: D002478:Cells, Cultured; D004921:Erythropoietin / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism*
chemical_list: D004921:Erythropoietin
keywords: Erk1/2; MAPK p38; erythropoietin-α; immune mediators; peripheral blood mononuclear cells; tumour necrosis factor alpha