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Etude des mécanismes cellulaires et moléculaires de l'inhibition de l'érythropoïèse par la cytokine pro-inflammatoire Tumor necrosis factor (TNF)-alpha

Abstract : Cancer-related anemia is thought to be mediated by the release of tumor necrosis factor (TNF[alpha]). TNF[alpha] is one of the major mediators of inflammation and has been linked to the inhibition of the erythropoietin (Epo) production from kidney, leading thus to anemia. However, the inhibitory effect of TNF[alpha] on erythroblast differentiation has been suggested by several in vitro studies. Previous results from the LBMCC lab on human leukemia cell lines showed that TNF[alpha] prevents over-expression of erythroid-specific genes in human erythroleukemia cell lines. In all cases, the inhibitory effect of TNF[alpha] was in correlation with the inhibition of the erythroid key transcription factor, GATA-1. In order to study the inhibitory effect of TNF[alpha] on the Epo-mediated erythropoiesis, we used CD34+ hematopoietic stem cells (HSC) as a model. In our in vitro model, we reproduced different stages of erythropoiesis, allowing us to use this model for the study of TNF[alpha] and the erythroid lineage. The study of hemoglobin production, the cell morphology and the analysis of specific erythroid membrane markers, have shown the limited capacity of Epo to stimulate HSC erythroid differentiation under TNF[alpha] treatment. At the molecular level, we have correlated this effect to the reduced expression of erythroid-specific genes. Moreover, TNF[alpha] reduces the transcriptional activity of GATA-1 and induces its interaction with PU.1 via p38MAPK activation. Furthermore, GATA-2 expression is increased and the GATA-1/GATA-2 balance, which is critical for erythropoiesis, is partially disturbed by 144/451 miRs inhibition from TNF[alpha]
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  • HAL Id : tel-01746269, version 1

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Christine Grigorakaki. Etude des mécanismes cellulaires et moléculaires de l'inhibition de l'érythropoïèse par la cytokine pro-inflammatoire Tumor necrosis factor (TNF)-alpha. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2011. Français. ⟨NNT : 2011NAN10106⟩. ⟨tel-01746269⟩

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