Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF-?± promote the NF-?oB-dependent maturation of normal and leukemic myeloid cells

摘要

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF-?± 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)-?oB activity and nuclear translocation of p75, p65, and p50 NF-?oB family members. Consistently, both cytokines also induced the degradation of the NF-?oB inhibitors, I?oB?± and I?oB?μ, and up-regulated the surface expression of TRAIL-R3, a known NF-?oB target. However, NF-?oB activation and I?oB degradation occurred with different time-courses, since TNF-?± 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 I?oB degradation, as demonstrated by using agonistic anti-TRAIL receptor antibodies. Moreover, NF-?oB nuclear translocation induced by TRAIL but not by TNF-?± was abrogated by z-IETD-fmk, a caspase-8-specific inhibitor. The key role of NF-?oB in mediating the biological effects of TNF-?± and TRAIL was demonstrated by the ability of unrelated pharmacological inhibitors of the NF-?oB pathway (parthenolide and MG-132) to abrogate TNF-?±- and TRAIL-induced monocytic maturation. These findings demonstrate that NF-?oB is essential for monocytic maturation and is activated via distinct pathways, involving or not involving caspases, by the related cytokines TRAIL and TNF-?±.