ZN2-STIMULATED SPHINGOMYELINASE IS SECRETED BY MANY CELL-TYPES AND ISA PRODUCT OF THE ACID SPHINGOMYELINASE GENE()

Mammalian sphingomyelinases have been implicated in many important phy siological and pathophysiological processes. Although several mammalia n sphingomyelinases have been identified and studied, one of these, an acidic Zn2+-stimulated sphingomyelinase (Zn-SMase) originally found i n fetal bovine serum, has received little attention since its first an d only report 7 years ago. We now show that Zn-SMase activity is secre ted by human and murine macrophages, human skin fibroblasts, microglia l cells, and several other cells in culture and is markedly up-regulat ed during differentiation of human monocytes to macrophages. Remarkabl y, peritoneal macrophages from mice in which the acid SMase gene had b een disrupted by homologous recombination secreted no Zn-SMase activit y, indicating that this enzyme and the intracellular lysosomal SMase, which is Zn-independent, arise from the same gene, Furthermore, skin f ibroblasts from patients with types A and B Niemann-Pick disease, whic h are known to lack lysosomal SMase activity, also lack Zn-SMase activ ity in their conditioned media. Chinese hamster ovary cells stably tra nsfected with a cDNA encoding lysosomal SMase massively overexpress bo th cellular lysosomal SMase and secreted Zn-SMase activities. Thus, Zn -SMase arises independently of alternative splicing, suggesting a post -translational process. In summary, a wide variety of cell types secre te Zn-SMase activity, which arises from the same gene as lysosomal SMa se. This secreted enzyme may play roles in physiological and pathophys iological processes involving extracellular sphingomyelin hydrolysis.