INVOLVEMENT OF NF-kB/IkBa PATHWAY IN TRAIL RESISTANCE OF HUMAN ERYTHROBLASTS

The biological activity of TNF-related apoptosis inducing lig- and (TRAIL) was analyzed on primary human erythroblasts derived from mononuclear cells of blood donors, kept in culture in the presence of 20% foetal calf serum, growth factors (EPO, SCF, IL-3) and glucocorticoids (10-6 Dexamethasone, 10-6 Oestradiol) or under growth factor and serum starvation. In the presence of growth factors and serum, primary ery- throblasts showed a differential expression of TRAIL-receptors (Rs) at various degrees of maturation and responded to TRAIL treatment with a mild cytotoxicity. Instead, in the absence of serum and growth factors,TRAIL treatment unexpectedly up- regulated TRAIL-R4 decoy receptor and promoted erythrob- lasts survival. The concomitant activation of NF-kB/IkB sur- vival pathway was detected with Western blotting and immuno- fluorescence procedures and confirmed by experiments per- formed with SN50, a pharmacological inhibitor of the NF- kB/IkB pathway. Our study indicates that TRAIL has a twofold activity on erythroid lineages since it mediates eythroid cells apoptosis in the presence of serum and growth factors, while it promotes erythroid cells survival through the activation of the NF-kB/IkB pathway under starvation conditions.