Interferon-γ Modulates Fetal Hemoglobin Synthesis in Sickle Cell Anemia and Thalassemia

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Abstract
Interferon-γ (IFN-γ) has been shown to influence globin gene expression in cord blood and normal adult progenitor-derived erythroblasts. To explore the influence of IFN-γ on fetal hemoglobin (HbF) synthesis in the hemoglobinopathies, erythroid progenitors (BFU-E, burst forming unit-erythroid) from patients with sickle cell anemia (SCA) and thalassemia were co-cultured with or without IFN-γ. Hemoglobin content in progenitor-derived erythroblasts was assessed by radioligand assay (RIA). Co-culture of erythroid progenitors from 12 SCA patients with 200–400 U/ml of IFN-γ resulted in a significant decrease in picograms of HbF and percent HbF per BFU-E-derived erythroblast. The mean decrease (±SEM) of picograms of HbF per cell and percent of HbF was by 42 ± 9% and 35 ± 8% of control cultures, respectively. Co-culture of erythroid progenitors from 10 patients with thalassemia major or thalassemia variant (HPFH/thalassemia, sickle/β0-thalassemia) with 200 U/ml IFN-γ also resulted in a significant decrease in picograms and percent of HbF per BFU-E-derived erythroblast. IFN-γ treatment also inhibited the enhancement in γ-globin synthesis induced in culture by butyric acid. Erythroid progenitors from 2 patients with SCA, 1 patient with sickle/β0-thalassemia, and 1 patient with HbE/β0-thalassemia were co-cultured with IFN-γ, L-α-amino-n-butyric acid, or both. HbF content (expressed as picograms HbF/cell) was decreased in samples co-cultured with IFN, increased in cultures with L-α-amino-n-butyric acid, but remained at control values in cultures treated with IFN plus L-α-amino-n-butyric acid. These data demonstrate that IFN-γ is an environmental factor that influences γ-globin gene expression in the β hemoglobinopathies in vitro.