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

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Abstract
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.
Funding Information
  • A.I.R.C.
  • C.I.B.
  • FIRB