The mechanism by which aluminium affects erythropoietin involves the hormone receptor.

VITTORI, D; PREGI, NICOLÁS; PÉREZ, G; ALFONSO G; NESSE, A

Congreso; Fifth Keele Meeting on Aluminium: "Aluminium in life: From acid rain to Alzheimer?s disease?; 2003

Erythropoietin (Epo) is the primary regulator of erythropoiesis, by promoting survival, proliferation and differentiation of erythroid progenitor cells. The first step of Epo-induced cell activation is the binding to its specific membrane receptor (EpoR) that triggers complex intracellular signals involving transient protein phosphorylation and activation of transcription factors. In previous works, we observed a steep reduction of erythroid progenitor cells when cultured in an aluminium (Al)-rich medium. The fact that this effect involves a depressed response to Epo suggested a mechanism of Al interference with the process of interaction between the hormone and its target cells. In the present work, we investigated the effect of Al on mechanisms of cell activation by Epo. We have employed two human erythroid cell lines, the Epo-independent K562 and the UT-7, strongly dependent of Epo to survive. A decreased amount of EpoR was found by immunoprecipitation and Western blot when K562 cells were incubated with Epo in the presence of Al. This finding was associated with a reduced mRNA level for EpoR, demonstrated by RT-PCR. Epo inhibited by 55 5% the programmed K562 cell death (apoptosis) induced by haemin, but the presence of Al reduced that protective effect of Epo. On the other hand, Al didn't affect the viability of UT-7 cells. Moreover, chronic Al treatment of this cells resulted in the enhancement of viable cell values sustained by Epo, and this agreed with the observation of increased EpoR expression, EpoR phosphorylation and EpoR mRNA levels. The results show that the effect of Al on Epo functions involves mechanisms related to its receptor. They are compatible with the existence of alternative signalling pathways for either Epo-induced cell proliferation or prevention of apoptosis. The behaviour of K562 cells, when cultured in the presence of Al, could partly explains the inhibitory effect of Al on erythroid progenitors (CFU-E), supporting the hypothesis that Epo is not involved in the commitment of the erythroid lineage, but rather, it might be a survival factor in order to allow cells to fulfil their differentiation program.