Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and tumor necrosis factor-a (TNF- a) promote the NF- kB-dependent maturation of both normal and leukemic myeloid cells.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF-alpha induced monocytic maturation of primary normal CD34-derived myeloid precursors and of the M2/M3-type acute myeloid leukemia HL-60 cell line, associated to increased nuclear factor (NF)-B activity and nuclear translocation of p75, p65, and p50 NF-B family members. Consistently, both cytokines also induced the degradation of the NF-B inhibitors, IB and IB, and up-regulated the surface expression of TRAIL-R3, a known NF-B target. However, NF-B activation and IB degradation occurred with different time-courses, since TNF-alpha was more potent, rapid, and transient than TRAIL. Of the two TRAIL receptors constitutively expressed by HL-60 (TRAIL-R1 and TRAIL-R2), only the former was involved in IB degradation, as demonstrated by using agonistic anti-TRAIL receptor antibodies. Moreover, NF-B nuclear translocation induced by TRAIL but not by TNF-alpha was abrogated by z-IETD-fmk, a caspase-8-specific inhibitor. The key role of NF-B in mediating the biological effects of TNF-alpha and TRAIL was demonstrated by the ability of unrelated pharmacological inhibitors of the NF-B pathway (parthenolide and MG-132) to abrogate TNF-alpha and TRAIL-induced monocytic maturation. These findings demonstrate that NF-B is essential for monocytic maturation and is activated via distinct pathways, involving or not involving caspases, by the related cytokines TRAIL and TNF-alpha.