title: Inhibition of mitochondrial function in HL60 cells is associated with an increased apoptosis and expression of CD14.
abstract: The myelomonocytic cell line HL60 can be induced by a variety of chemical agents to differentiation to either neutrophils or monocytes. Examination of gene expression, by differential display, in cells induced to monocytes with 1alpha,25-dihydroxyvitamin D(3) or neutrophils with all-trans retinoic acid (ATRA) identified a number of clones with altered patterns of expression over the period of differentiation. One of these clones was the mitochondrial gene NADH dehydrogenase subunit 4 (ND4) which showed a differential pattern of expression between the neutrophil and monocyte lineages. The potential of mitochondrial inhibitors to induce differentiation was investigated by treating the HL60 cells with either the NADH dehydrogenase inhibitor, Rotenone, the complex III inhibitor, Antimycin A, or the highly specific mitochondrial ATP-synthase inhibitor, Oligomycin. Although functional assays of differentiation did not produce any positive results, all the inhibitors resulted in a dramatic increase in CD14 expression at day 1, with CD38 markers not observed until day 3. The increased expression of CD14 was accompanied by a decrease in viability and all CD14 positive cells were also positive for Annexin V, a marker of apoptosis. These results suggest that inhibition of the components of the mitochondrial pathways may lead to the marking of some cells, via CD14, for cell death, whilst allowing commitment to differentiation to occur in the surviving population.
authors.affiliation: Department of Haematology, University of Wales College of Medicine, Cardiff, Heath Park, United Kingdom. whgkim@cardiff.ac.uk
authors.forename: K I
authors.initials: KI
authors.lastname: Mills
authors.forename: L J
authors.initials: LJ
authors.lastname: Woodgate
authors.forename: A F
authors.initials: AF
authors.lastname: Gilkes
authors.forename: V
authors.initials: V
authors.lastname: Walsh
authors.forename: M C
authors.initials: MC
authors.lastname: Sweeney
authors.forename: G
authors.initials: G
authors.lastname: Brown
authors.forename: A K
authors.initials: AK
authors.lastname: Burnett
mesh_terms: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D017304:Annexin A5 / Q000096:biosynthesis; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis; D000968:Antimycin A / Q000494:pharmacology; D017209:Apoptosis; D002117:Calcitriol / Q000494:pharmacology; D002454:Cell Differentiation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D018922:HL-60 Cells / Q000187:drug effects*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy; D007962:Leukocytes / Q000166:cytology* / Q000187:drug effects; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis*; D008562:Membrane Glycoproteins; D008928:Mitochondria / Q000187:drug effects*; D009000:Monocytes / Q000166:cytology; D009244:NAD+ Nucleosidase / Q000096:biosynthesis; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000166:cytology; D009840:Oligomycins / Q000494:pharmacology; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D012402:Rotenone / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D017304:Annexin A5; D015703:Antigens, CD; D000943:Antigens, Differentiation; D004791:Enzyme Inhibitors; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D009840:Oligomycins; D014475:Uncoupling Agents; D012402:Rotenone; D014212:Tretinoin; D000968:Antimycin A; D009245:NADH Dehydrogenase; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D006180:Proton-Translocating ATPases; D002117:Calcitriol