title: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF-alpha promote the NF-kappaB-dependent maturation of normal and leukemic myeloid cells.
abstract: 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)-kappaB activity and nuclear translocation of p75, p65, and p50 NF-kappaB family members. Consistently, both cytokines also induced the degradation of the NF-kappaB inhibitors, IkappaBalpha and IkappaB epsilon, and up-regulated the surface expression of TRAIL-R3, a known NF-kappaB target. However, NF-kappaB activation and IkappaB 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 IkappaB degradation, as demonstrated by using agonistic anti-TRAIL receptor antibodies. Moreover, NF-kappaB 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-kappaB in mediating the biological effects of TNF-alpha and TRAIL was demonstrated by the ability of unrelated pharmacological inhibitors of the NF-kappaB pathway (parthenolide and MG-132) to abrogate TNF-alpha- and TRAIL-induced monocytic maturation. These findings demonstrate that NF-kappaB is essential for monocytic maturation and is activated via distinct pathways, involving or not involving caspases, by the related cytokines TRAIL and TNF-alpha.
authors.affiliation: Department of Morphology and Embryology, Human Anatomy Section, St. Anna Hospital, University of Ferrara, Italy. secchier@mail.umbi.umd.edu
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
authors.forename: Daniela
authors.initials: D
authors.lastname: Milani
authors.forename: Arianna
authors.initials: A
authors.lastname: Gonelli
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Melloni
authors.forename: Diana
authors.initials: D
authors.lastname: Campioni
authors.forename: Davide
authors.initials: D
authors.lastname: Gibellini
authors.forename: Silvano
authors.initials: S
authors.lastname: Capitani
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
mesh_terms: D000208:Acute Disease; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058851:GPI-Linked Proteins; D018922:HL-60 Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D009000:Monocytes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D011994:Recombinant Proteins / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D017304:Annexin A5; D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C108661:TNFRSF10C protein, human; C505653:TNFSF10 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases