Pro-Inflammatory Cytokine-Mediated Anemia: Regarding Molecular Mechanisms of Erythropoiesis
TNF α inhibits erythropoiesis by direct and indirect effects. In the indirect effect, TNFα activates the transcription factors NF-B and GATA-2, which were also reported as involved in Epo production inhibition by blocking HIF1α in vitro. Low level of Epo decreases the EpoR-mediated signaling pathways resulting among others, in the down-regulation of GATA-1, and consequently in a possible deregulation of EpoR expression. The direct effect of TNFα via its receptors TNFR1/2 has also been demonstrated. The activation of the NF-B canonical pathway (p50/p65) inhibits erythro-specific genes expression as globin genes. TNFα was also reported as activating GATA-2 whose over-expression is known to prohibit erythropoiesis in favor of megakaryopoiesis. Conversely, TNFα inhibits GATA-1 in K562, HEL and TF1 cells. GATA-1 expression is affected as well as its acetylation (Ac), and its interaction with FOG1 that was suggested to be degraded by proteasome. Moreover, TNFα was shown to rapidly stimulate p38MAPK phosphorylation in correlation with -globin gene down-expression while Epo had a delayed effect on this kinase activation. The combined effects of TNFα result in the decrease in erythro-specific genes expression and hemoglobin production.
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