Interleukin-6 directly impairs the erythroid development of human TF-1 erythroleukemic cells

Abstract

Anemia of inflammation or chronic disease is a highly prevalent form of anemia. The inflammatory cytokine interleukin-6 (IL-6) negatively correlates with hemoglobin concentration in many disease states. The IL-6-hepcidin antimicrobial peptide axis promotes iron-restricted anemia; however the full role of IL-6 in anemia of inflammation is not well-defined. We previously reported that chronic inflammation had a negative impact on maturation of erythroid progenitors in a mouse model. We hypothesized that IL-6 may be responsible for impaired erythropoiesis, independent of iron restriction. To test the hypothesis we utilized the human erythroleukemia TF-1 cell line to model erythroid maturation and exposed them to varying doses of IL-6 over six days. At 10 ng/ml, IL-6 significantly repressed erythropoietin-dependent TF-1 erythroid maturation. While IL-6 did not decrease the expression of genes associated with hemoglobin synthesis, we observed impaired hemoglobin synthesis as demonstrated by decreased benzidine staining. We also observed that IL-6 down regulated expression of the gene SLC4a1 which is expressed late in erythropoiesis. Those findings suggested that IL-6-dependent inhibition of hemoglobin synthesis might occur. We investigated the impact of IL-6 on mitochondria. IL-6 decreased the mitochondrial membrane potential at all treatment doses, and significantly decreased mitochondrial mass at the highest dose. Our studies indicate that IL-6 may impair mitochondrial function in maturing erythroid cells resulting in impaired hemoglobin production and erythroid maturation. Our findings may indicate a novel pathway of action for IL-6 in the anemia of inflammation, and draw attention to the potential for new therapeutic targets that affect late erythroid development.

Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus

“…31 Additionally TNF-a and IL-10 have an effect on cellular iron homeostasis. 32,33 Moreover, recent findings by McCranor et al 34 support the role of IL-6 in reducing erythropoiesis independently of iron Many translational studies focused at neutralizing Hamp overexpression as a therapy against AI. However, due to their direct role on erythropoiesis and iron metabolism, cytokines could represent a potential therapeutic target as well.…”

Hepcidin regulation in the anemia of inflammation

“…IL6 knockout mice were also partially protected against AI in the BA model, and exhibited faster recovery of erythropoiesis, suggesting a distinct role for IL6 in AI pathophysiology by suppressing erythropoiesis [29*]. Recently, IL6 was demonstrated to reduce mitochondrial membrane potential in an erythroleukemic cell line to impair hemoglobin production and erythroid maturation, suggesting at least one mechanism for IL6 to inhibit erythropoiesis [32]. Although these animal models have some limitations, they are valuable tools to dissect the pathophysiology of AI and test new therapeutic strategies.…”

Role of hepcidin‐ferroportin axis in the pathophysiology, diagnosis, and treatment of anemia of chronic inflammation

“…IL‐6 induction of hepcidin expression is mediated through STAT3 signaling in hepatocytes. More recent data suggests that IL‐6 may have a secondary suppressive effect on erythroid precursors . In addition, the loss of IL‐6 and hepcidin in mice results in a milder anemia and more rapid recovery of hemoglobin in a well‐established mouse model of ACI .…”