Pro-inflammatory cytokine-mediated anemia: regarding molecular mechanisms of erythropoiesis

Abstract

Anemia of cancer and chronic inflammatory diseases is a frequent complication affecting quality of life. For cancer patients it represents a particularly bad prognostic. Low level of erythropoietin is considered as one of the causes of anemia in these pathologies. The deficiency in erythropoietin production results from pro-inflammatory cytokines effect. However, few data is available concerning molecular mechanisms involved in cytokine-mediated anemia. Some recent publications have demonstrated the direct effect of pro-inflammatory cytokines on cell differentiation towards erythroid pathway, without erythropoietin defect. This suggested that pro-inflammatory cytokine-mediated signaling pathways affect erythropoietin activity. They could interfere with erythropoietin-mediated signaling pathways, inducing early apoptosis and perturbing the expression and regulation of specific transcription factors involved in the control of erythroid differentiation. In this review we summarize the effect of tumor necrosis factor (TNF)alpha, TNF-related apoptosis-inducing ligand (TRAIL), and interferon (IFN)-gamma on erythropoiesis with a particular interest for molecular feature.

Figure 1

TNF α inhibits erythropoiesis by direct and indirect effects. In the indirect effect, TNFα activates the transcription factors NF-κB 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-κB 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 γ-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.