A large number of constituents, such as growth factors, cytokines, and vasoregulatory molecules, contribute a network of cellular interactions to atherosclerotic lesions, and current evidence suggests that granulocyte-macrophage colony-stimulating factor (GM-CSF) is one of these constituents. We conducted 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 in vitro with a highly inducible HL60 subclone (HL60/DU-1) that we recently established. HL60 cells have been reported to preserve functional GM-CSF receptors, 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 differentiation of macrophages by 1, 25-dihydroxy vitamin D(3) treatment. We found cell death to be mediated mainly by necrosis, not apoptosis, as confirmed by DNA fragmentation in agarose gel electrophoresis, morphological observation under a fluorescence microscope, and assay of lactate dehydrogenase release. Exogeneously administered GM-CSF rescued cells from necrotic death and caused them to survive and generate superoxide anions. We also conducted immunohistochemical analysis on an atherosclerotic human artery. Macrophages, endothelial cells, and smooth muscle cells were found to be GM-CSF positive in an atherosclerotic lesion. In summary, GM-CSF, which is produced by macrophages, endothelial cells, and smooth muscle cells, is thought to act in an autocrine and a paracrine fashion as a necrosis-inhibiting factor against arterial macrophages. This unique function may play an important role in ensuring survival and promoting function in atherosclerotic lesions.