Functional Links Between Glucocorticoids and Cytokines In DBA

Abstract

Diamond Blackfan anaemia (DBA) is a red blood cell aplasia characterized by erythropoietic defects as well as congenital anomalies. Forty percent of patients with DBA are treated with glucocorticoid steroids, which remain the mainstay of treatment in DBA. Many advances in the understanding of the physiological role of the glucocorticoid receptor have been made since the first introduction of glucocorticoids to the clinic, but their mechanism of action in the treatment of DBA is still under investigation. This review is intended to summarize the mechanism of glucocorticoid action specifically as related to erythropoiesis, focusing on the functional links between glucocorticoids and cytokines. IntroductionDiamond Blackfan anemia (DBA) was first described as a disorder of impaired red blood cell production in children [1,2]. While most of the DBA cases are diagnosed in early infancy, a recent case report reveals that DBA can occur during fetal development. This suggests that severely affected DBA fetus likely die to hydrops fetalis and result in undiagnosed miscarriages [3]. This disorder results from a cellular defect in which erythroid progenitors are highly sensitive to death by apoptosis, leading to erythropoietic failure [4]. The etiology of DBA has been the subject of continuous discussions, and while the early success of treatment with glucocorticoids (GCs) in 1951 [5] led to the idea that the pathogenesis of DBA could have an immunologic basis [6], it is now accepted that DBA is in fact a member of a rare group of genetic disorders.Approximately 50% of DBA patients have a single mutation in a gene encoding a ribosomal protein, which indicates that DBA is associated with a disorder of ribosome biogenesis and/or function [4]. The pronounced erythroid defect suggests that erythroid progenitors may express specific mRNAs that are hypersensitive to the decreased translation capacity [7]. Twenty-five percent of patients have a mutation in the ribosomal protein S19 (RPS19) gene [8], and two independent studies have demonstrated that over expression of the RPS19 transgene increases the number of erythroid colonies in RPS19 deficient hematopoietic progenitor cells in vitro [9,10]. In a mouse model of DBA, a high expression of RPS19 can rescue the erythroid development, and the corrected DBA cells show a survival advantage in vivo [11]. As zebrafish hematopoietic regulation is conserved with mammals, zebrafish models have also been reported to be useful in studying DBA [12][13][14], recapitulating many aspects of the DBA phenotype, including hematopoietic specific defects and p53 activation [14]. The list of genes that are mutated in DBA has been updated in 2013, to include ten ribosomal genes and one transcriptional regulator: RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS10, RPS26, RPL26, and GATA1 [15].More than 50 years after their introduction to the clinic, GCs are still the most effective drugs used in DBA. Nevertheless, the reported side effects of GCs include decreased growth velocity in infants...