Sphingolipids and Monocyte/Macrophage Differentiation of HL-60 Cells

Abstract

The human promyelocytic leukemia HL-60 cell line has been used extensively to investigate differentiation along the monocyte/macrophage pathway. Phorbol esters induce macrophage differentiation via protein kinase C and vitamin D, tumor necrosis factor-α and γ-interferon induce monocyte differentiation. Distinct patterns of sphingolipid metabolism have been associated with these events. Macrophage differentiation is accompanied by a selective increase in ganglioside G_M3 which may mediate crucial aspects of the differentiation program. Macrophage differentiation also involves synthesis of sphingomyelin, which precedes adherence and may directly be involved in the adherence process. In contrast, sphingomyelin degradation via the action of a neutral sphingomyelinase may be involved in monocytic differentiation. In this paradigm, ceramide may function as second messenger. Recent advances also include the discovery of ceramide 1-phosphate and the associated calcium-dependent kinase, ceramide kinase in these cells. The biologic role of ceramide 1-phosphate and the regulation of the kinase are at present undefined. The notion that a sphingomyelin pathway analogous to the phosphoinositide pathway may exist initiated by the action of a sphingomyelinase is presented. These early investigations suggest that biologically relevant signals may be flowing into and out of sphingomyelin.