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

Tohru Ikuta, Adekunle D. Adekile, Diana Raisovna Gutsaeva, James B. Parkerson, Shobha D. Yerigenahally, Betsy Clair, Abdullah Kutlar, Nadine Odo, C. Alvin Head

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 the 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 of 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 count 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.

Original languageEnglish (US)
Pages (from-to)235-242
Number of pages8
JournalBlood Cells, Molecules, and Diseases
Volume47
Issue number4
DOIs
StatePublished - Dec 15 2011

Fingerprint

Fetal Hemoglobin
Sickle Cell Anemia
Granulocyte-Macrophage Colony-Stimulating Factor
Down-Regulation
Cytokines
Hydroxyurea
Leukocyte Count
Erythroid Cells
Phosphorylation
Therapeutics
Cyclic AMP Response Element-Binding Protein
Erythroblasts
Mitogen-Activated Protein Kinases

Keywords

  • CAMP
  • Fetal hemoglobin
  • GM-CSF
  • Leukocytosis
  • Sickle cell disease

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Hematology
  • Cell Biology

Cite this

The proinflammatory cytokine GM-CSF downregulates fetal hemoglobin expression by attenuating the cAMP-dependent pathway in sickle cell disease. / Ikuta, Tohru; Adekile, Adekunle D.; Gutsaeva, Diana Raisovna; Parkerson, James B.; Yerigenahally, Shobha D.; Clair, Betsy; Kutlar, Abdullah; Odo, Nadine; Head, C. Alvin.

In: Blood Cells, Molecules, and Diseases, Vol. 47, No. 4, 15.12.2011, p. 235-242.

Research output: Contribution to journalArticle

Ikuta, Tohru ; Adekile, Adekunle D. ; Gutsaeva, Diana Raisovna ; Parkerson, James B. ; Yerigenahally, Shobha D. ; Clair, Betsy ; Kutlar, Abdullah ; Odo, Nadine ; Head, C. Alvin. / The proinflammatory cytokine GM-CSF downregulates fetal hemoglobin expression by attenuating the cAMP-dependent pathway in sickle cell disease. In: Blood Cells, Molecules, and Diseases. 2011 ; Vol. 47, No. 4. pp. 235-242.
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AU - Parkerson, James B.

AU - Yerigenahally, Shobha D.

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AU - Odo, Nadine

AU - Head, C. Alvin

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