The proinflammatory
cytokine tumor necrosis factor alpha (
TNFalpha) has been linked to
inflammation- and
cancer-related
anemia, which reduces both quality of life and prognosis of patients. The aim of this study was to reveal molecular mechanisms linked to the inhibition of erythroid differentiation by
TNFalpha. In this study, we showed that the inhibition of
erythropoietin (Epo)-mediated differentiation by
TNFalpha lead to a downregulation of
hemoglobin synthesis and was correlated to a modulation of key erythroid
transcription factors. Thus, a reverse of the
transcription factor GATA-1/GATA-2 balance normally present during erythropoiesis, as well as a downregulation of the cofactor of GATA-1, friend of GATA-1 (FOG-1), and the coregulating
transcription factor nuclear factor erythroid 2 (NF-E2) was observed after
TNFalpha treatment. Moreover, we showed a reduction of GATA-1/FOG-1 interaction due to a reduced transcription of GATA-1 and a
proteasome-dependent FOG-1 degradation after
TNFalpha treatment. These changes led to an inhibition of erythroid gene expression including Epo receptor (EpoR), alpha- and
gamma-globin, erythroid-associated factor (ERAF),
hydroxymethylbilane synthetase (HMBS), and
glycophorin A (GPA). An analysis of distinct signaling pathway activations then revealed an activation of p38 by TNF, as well as a corresponding involvement of this
mitogen-activated protein kinase (MAPK) in the
cytokine-dependent inhibition of erythroid differentiation. Indeed the p38 inhibitor,
SB203580, abrogated the inhibitory effect of
TNFalpha on the major erythroid
transcription factor GATA-1 as well as erythroid marker expression in Epo-induced TF-1 cells. Overall, these data contribute to a better understanding of
cytokine-dependent
anemia, by giving first hints about key erythroid
transcription factor modulations after
TNFalpha treatment as well as an involvement of p38 in the inhibition of erythroid differentiation.