Granulocyte-macrophage, colony-stimulating factor ensures macrophage survival and generation of the superoxide anion: A study using a monocytic-differentiated HL60 subline
M. Ujihara et al., Granulocyte-macrophage, colony-stimulating factor ensures macrophage survival and generation of the superoxide anion: A study using a monocytic-differentiated HL60 subline, FREE RAD B, 31(11), 2001, pp. 1396-1404
A large number of constituents, such as growth factors, cytokines, and vaso
regulatory molecules, contribute a network of cellular interactions to athe
rosclerotic lesions, and current evidence suggests that granulocyte-macroph
age colony-stimulating factor (GM-CSF) is one of these constituents. We con
ducted this study to determine whether GM-CSF has an effect on the fate and
function of macrophages. We examined the effect of GM-CSF on macrophages i
n vitro with a highly inducible HL60 subclone (HL60/DU-1) that we recently
established. HL60 cells have been reported to preserve functional GM-CSF re
ceptors, but a GM-CSF allele was rearranged and partially deleted. HL60/DU-
1 cells were devoid of GM-CSF immunoreactivity and of autocrine stimulation
of GM-CSF. HL60/DU-1 cells fated to die soon after terminal differentiatio
n of macrophages, by 1, 25-dihydroxy vitamin D-3 treatment. We found cell d
eath to be mediated mainly by necrosis, not apoptosis, as confirmed by DNA
fragmentation in agarose gel electrophoresis, morphological observation und
er a fluorescence microscope, and assay of lactate dehydrogenase release. E
xogeneously administered GM-CSF rescued cells from necrotic death and cause
d them to survive and generate superoxide anions. We also conducted immunoh
istochemical analysis on an atherosclerotic human artery. Macrophages, endo
thelial cells, and smooth muscle cells were found to be GM-CSF positive in
an atherosclerotic lesion. In summary, GM-CSF, which is produced by macroph
ages, endothelial cells, and smooth muscle cells, is thought to act in an a
utocrine and a paracrine fashion as a necrosis-inhibiting factor against ar
terial macrophages. This unique function may play an important role in ensu
ring survival and promoting function in atherosclerotic lesions. (C) 2001 E
lsevier Science Inc.