Effects of p38 MAP Kinase Inhibitors on the Differentiation and Maturation of Erythroid Progenitors

Abstract

In rodents, p38 MAP kinase inhibitors (p38is) induce bone marrow hypocellularity and reduce reticulocyte and erythrocyte counts. To identify target cell populations affected, a differentiating primary liquid erythroid culture system using sca-1 + cells from mouse bone marrow was developed and challenged with p38is SB-203580, SB-226882, and SB-267030. Drug-related alterations in genes involved at different stages of erythropoiesis, cell-surface antigen expression (CSAE), burst-forming unit erythroid (BFU-E) colony formation, and cellular morphology (CM), growth (CG), and viability were evaluated. CSAE, CM, and decreases in BFU-E formation indicated delayed maturation, while CG and viability were unaffected. Terminal differentiation was delayed until day 14 versus day 7 in controls. CSAE demonstrated higher percentages of sca-1 + cells after day 2 and reduced percentages of ter119 + cells after day 7 in all treated cultures. Real-time reverse transcriptase polymerase chain reaction revealed a transient delay in expression of genes involved at early, intermediate, and late stages of erythropoiesis, followed by rebound expression at later time points. Results demonstrate p38is do not irreversibly inhibit erythrogenesis but induce a potency-dependent, transient delay in erythropoietic activity. The delay in activity is suggestive of effects on sca-1 + bone marrow cells caused by alterations in expression of genes related to erythroid commitment and differentiation resulting in delayed maturation.

The Effects of p38 MAPK Inhibition Combined with G-CSF Administration on the Hematoimmune System in Mice with Irradiation Injury

“…These findings suggest that G-CSF treatment might be important in promoting the recovery of hematopoiesis immediately after TBI, which is consistent with the previous reports [27], [28], [29], [30]. It has been shown that p38 inhibition can modulate hematopoiesis as well [31]. In this study, we found that inhibition of p38 with SB alone promoted the recovery of WBC, RBC and PLT at 30d post irradiation, but its effects were not significant at 10d post irradiation.…”

MAPK p38alpha Kinase Influences Haematopoiesis in Embryonic Stem Cells

“…Therefore, we analysed the expression of other markers which can be associated with hematopoietic stem/progenitor cells. Unexpectedly, the expressions of Sca1 and c-Kit were increased in contrast to the overall decrease in haematopoiesis in p38 α −/− cells but this could be explained as a delay in the differentiation process [14, 57]. In contrast, lower expressions of CD34 transcripts in mutant cells mark a decrease in hematopoietic potential.…”

“…Previously, it was shown that EPO activity is mediated by p38 α kinase and that p38 α kinase is required for EPO mRNA stability and hemoglobin synthesis. Moreover, the inhibition of p38 α leads to the blocking of the EPO-dependent accumulation of mouse globin chains in erythroid precursors [14, 57]. Also, erythrocyte maturation is impaired not only by defects in EPO/EpoR downstream signaling but also by a low level of EpoR transcript, the expression of which is induced by GATA1 [61].…”

Identification of signalling cascades involved in red blood cell shrinkage and vesiculation

“…Using the inhibitors SB203580 and p38 MAPK inhibitor III they showed that inhibition of p38 kinase leads to reduced PS exposure upon hyperosmotic shock or ionomycin stimulation [ 63 ]. Other studies employing pan p38 inhibitors demonstrate that p38 MAPK inhibition induces a transient delay in murine erythropoiesis [ 64 ]. In vivo experiments with p38 MAPK knockout mice show that mice die in utero or survive owing to severe anaemia due to defective erythropoiesis resulting from reduced erythropoietin (Epo) levels [ 65 ].…”