Interferon-gamma modulates fetal hemoglobin synthesis in sickle cell anemia and thalassemia.
Interferon-gamma (IFN-gamma) has been shown to influence globin gene expression in cord blood and normal adult progenitor-derived erythroblasts. To explore the influence of IFN-gamma 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-gamma. 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-gamma 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/beta 0-thalassemia) with 200 U/ml IFN-gamma also resulted in a significant decrease in picograms and percent of HbF per BFU-E-derived erythroblast. IFN-gamma treatment also inhibited the enhancement in gamma-globin synthesis induced in culture by butyric acid. Erythroid progenitors from 2 patients with SCA, 1 patient with sickle/beta 0-thalassemia, and 1 patient with HbE/beta 0-thalassemia were co-cultured with IFN-gamma, L-alpha-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-alpha-amino-n-butyric acid, but remained at control values in cultures treated with IFN plus L-alpha-amino-n-butyric acid. These data demonstrate that IFN-gamma is an environmental factor that influences gamma-globin gene expression in the beta hemoglobinopathies in vitro.
Miller
B A
BA
Division of Pediatric Hematology/Oncology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17033.
Olivieri
N
N
Hope
S M
SM
Faller
D V
DV
Perrine
S P
SP
D000613:Aminobutyrates / Q000494:pharmacology; D000755:Anemia, Sickle Cell / Q000378:metabolism*; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000096:biosynthesis*; D005914:Globins / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D011869:Radioligand Assay; D011994:Recombinant Proteins; D013789:Thalassemia / Q000378:metabolism*
D000613:Aminobutyrates; D011994:Recombinant Proteins; D007371:Interferon-gamma; C012223:alpha-aminobutyric acid; D005914:Globins; D005319:Fetal Hemoglobin