The proinflammatory cytokine GM-CSF downregulates fetal hemoglobin expression by attenuating the cAMP-dependent pathway in sickle cell disease

Abstract

Although reduction in leukocyte counts following hydroxyurea therapy in sickle cell disease (SCD) predicts fetal hemoglobin (HbF) response, the underlying mechanism remains unknown. We previously reported that leukocyte counts are regulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) in SCD patients. Here we examined the roles of GM-CSF in the regulation of HbF expression in SCD. Upon the analysis of retrospective data in 372 patients, HbF levels were inversely correlated with leukocyte counts and GM-CSF levels in SCD patients without hydroxyurea therapy, while HbF increments after hydroxyurea therapy correlated with a reduction in leukocyte counts, suggesting a negative effect of GM-CSF on HbF expression. Consistently, in vitro studies using primary erythroblasts showed that addition of GM-CSF to erythroid cells decreased HbF expression. We next examined the intracellular signaling pathway through which GM-CSF reduced HbF expression. Treatment of erythroid cells with GM-CSF resulted in the reduction in intracellular cAMP levels and abrogated phosphorylation of cAMP response-element-binding-protein, suggesting attenuation of the cAMP-dependent pathway, while the phosphorylation levels of mitogen-activated protein kinases were not affected. This is compatible with our studies showing a role for the cAMP-dependent pathway in HbF expression. Together, these results demonstrate that GM-CSF plays a role in regulating both leukocyte counts and HbF expression in SCD. Reduction in GM-CSF levels upon hydroxyurea therapy may be critical for efficient HbF induction. The results showing the involvement of GM-CSF in HbF expression may suggest possible mechanisms for hydroxyurea resistance in SCD.

Genetic variants at HbF‐modifier loci moderate anemia and leukocytosis in sickle cell disease in Tanzania

“…The beneficial effects of higher HbF on hematological parameters, such as a higher Hb, lower WBC, and platelet counts, have previously been described in Jamaica , but might be less evident in a setting where the most‐severely anemic patients are transfused regularly. The reduction in anemia we saw in patients with higher HbF levels was paralleled by an increase in two RBC indices (MCV and MCH), while RBC numbers were unchanged.…”

Randomized feasibility trial to improve hydroxyurea adherence in youth ages 10–18 years through community health workers: The HABIT study

“…Effects of HU are largely through induction of a dose‐dependent increase in fetal hemoglobin (HbF). Anti‐inflammatory effects of HU also contribute to its clinical impact, such as reducing neutrophil count and inflammatory mediators …”

Proteomic Insight Reveals Elevated Levels of Albumin in Circulating Immune Complexes in Diabetic Plasma

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