Opposite effect of TNF‐alpha and activin A on erythroid gene expression through different pathways in hematopoietic progenitor cells

Abstract

Cancer and inflammation related anemia is mediated by proinflammatory cytokines. However, the molecular mechanism of this cytokines‐inhibited erythropoiesis remains unclear. This study shows that proinflammatory cytokines, TNF‐α and IFN‐γ, inhibit activin A‐activated ζ‐globin promoter, but not IL‐1α, IL‐10 and IL‐13 in hematopoieticprogenitor cell line K562. The p38 inhibitor SB203580 decreases activin A‐activated ζ‐globin promoter, but did not alter the effects of TNF‐α and IFN‐γ. The NF‐κB inhibitor Bay117082 reduces TNF‐α‐ and IFN‐γ‐inhibited ζ‐globin promoter activity, but did not alter the effects of activin A. Activin A inhibits c‐Jun expression, c‐Jun binding to AP‐1 binding sites of c‐Jun promoter and c‐Jun promoter activity through p38 pathway. TNF‐α induces c‐Jun expression to reverse activin A inhibitory effects via NF‐κB/c‐Jun complex binding to AP‐1 bonding sites of c‐Jun promoter. Furthermore, wild‐type c‐Jun enhances and c‐Jun dominant negative mutant eliminates TNF‐α‐inhibited ζ‐globin promoter activity. Thus, activin A down‐regulates c‐Jun through p38 to induce globin gene expression. TNF‐α activates NF‐κB/c‐Jun to inhibit the effects of activin A on hematopoieticprogenitor cells.