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

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