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Prepublished online as a Blood First Edition Paper on September 11, 2003; DOI 10.1182/blood-2003-06-2137.
Submitted July 8, 2003
Accepted August 28, 2003
TRAIL regulates normal erythroid maturation through an ERK-dependent pathway
Paola Secchiero*, Elisabetta Melloni, Markku Heikinheimo, Susanna Mannisto, Roberta Di Pietro, Antonio Iacone, and Giorgio Zauli
Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, Ferrara, Italy
Biomedicum Helsinki, Program for Developmental and Reproductive Biology, University of Helsinki, Helsinki, Finland
Department of Normal Human Morphology, University of Trieste, Trieste, Italy
Department of Transfusion Medicine Study Center, Santo Spirito Hospital of Pescara, Pescara, Italy
* Corresponding author; email: secchier{at}mail.umbi.umd.edu.
In order to investigate the biological activity of TRAIL on human erythropoiesis, glycophorin A (GPA)+ erythroid cells were generated in serum-free liquid phase from human cord blood (CB) CD34+ progenitor cells. The surface expression of TRAIL-R1 was weakly detectable in the early-intermediate phase of erythroid differentiation (days 4-6; dim-intermediate GPA expression), whereas a clear-cut expression of TRAIL-R2 was observed through the entire course of erythroid differentiation (up to days 12-14; bright GPA expression). On the other hand, surface TRAIL-R3 and -R4 were not detected at any culture time. Besides inducing a rapid but small increase of apoptotic cell death, which was abrogated by the pan-caspase inhibitor z-VAD-fmk, the addition of recombinant TRAIL at day 6 of culture inhibited the generation of morphologically mature erythroblasts. Among the intracellular pathways investigated, TRAIL significantly stimulated the ERK1/2 but not the p38/MAPK or the JNK pathway. Consistently with a key role of ERK1/2 in mediating the negative effects of TRAIL on erythroid maturation, PD98059, a pharmacological inhibitor of the ERK pathway, but not z-VAD-fmk or SB203580, a pharmacological inhibitor of p38/MAPK, reverted the anti-differentiative effect of TRAIL on CB-derived erythroblasts.
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