Tumor necrosis factor-related apoptosis-inducing ligand induces monocytic maturation of leukemic and normal myeloid precursors through a caspase-dependent pathway.
Treatment of the human HL-60 cell line with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resulted in rapid (6-24 hours) cytotoxicity associated with progressive maturation of the surviving cells along the monocytic lineage. The occurrence of monocytic maturation was demonstrated by a significant increase of both CD14 and CD11b surface expression, the acquisition of morphologic features typical of mature monocytes, and phagocytic capacity in TRAIL-treated cultures. By using selective pharmacologic inhibitors, it was possible to demonstrate that activation of the caspase cascade played a crucial role in mediating TRAIL cytotoxicity and monocytic maturation of HL-60 cells. Moreover, experiments performed using agonistic polyclonal antibodies, which mimic the interactions between TRAIL and each TRAIL receptor, indicated that TRAIL-R1 was responsible for mediating the TRAIL-induced maturation. Importantly, the maturational effects of TRAIL were observed also in primary normal CD34(+) cells, seeded in serum-free liquid cultures for 4 to 8 days in the presence of SCF + GM-CSF. After treatment with TRAIL for 3 additional days, a significant increase in CD14 and CD11b expression, coupled with an increased number of mature monocytes and macrophages, was noticed in the absence of cytotoxicity. These data disclose a novel role for TRAIL as a positive regulator of myeloid differentiation. Moreover, the dichotomous effect of TRAIL on malignant cells (early induction of apoptosis and monocytic maturation of the surviving cells) might have important therapeutic implications for the treatment of acute myeloid leukemia.
Secchiero
Paola
P
Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, Italy. secchier@mail.umbi.umd.edu
Gonelli
Arianna
A
Mirandola
Prisco
P
Melloni
Elisabetta
E
Zamai
Loris
L
Celeghini
Claudio
C
Milani
Daniela
D
Zauli
Giorgio
G
D015703:Antigens, CD / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D039481:CD11b Antigen / Q000032:analysis; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival; D017931:DNA Primers; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology*; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D039481:CD11b Antigen; D017931:DNA Primers; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases