Selective effects of glucocerebroside (Gaucher's storage material) on macrophage cultures

Although the enzymatic lesion in Gaucher's disease is well established, little is known concerning the pathogenic mechanisms involved in the clinical manifestations of the disease. In order to obtain insight into this unexplored aspect of Gaucher's disease, we examined the effects of glucocerebroside (GL(1)) at the cellular level in monolayers of cultured murine macrophages. The addition of GL(1) to these cultures stimulated the macrophages to release increased amounts of lymphocyte-activating factor (LAF) and lysosomal enzymes into the medium. These responses were proportional to the amount of GL(1) added to the culture. At higher levels of GL(1) (>/=20 mug/ml), lactic dehydrogenase, a cytoplasmic enzyme was also released indicating cellular damage at these doses. Intracellular LAF also increased in macrophages incubated with the high doses of GL(1), demonstrating an increase in total LAF production by these cells. Lipopolysaccharide acted synergistically with GL(1) and stimulated the release of exceedingly high levels of LAF which had a molecular weight profile similar to that of LAF released by exposure to lipopolysaccharide alone. Unlike GL(1), galactocerebroside, sphingomyelin, and ceramidetrihexoside, exerted little or no effect on the release of macrophage products. The effect of GL(1) was selective for macrophages since addition of this material to mouse lens epithelial cells had no detectable cytotoxic effect and it was only slightly toxic to lymphocytes or P815 cells in concentrations at which macrophages were clearly affected. A direct relationship was observed between the cytotoxicity of the sphingolipids and their accumulation in various cells. Macrophages accumulated large amounts of GL(1) but not sphingomyelin, whereas the other cells examined in this investigation did not accumulate either of these lipids. Human monocytes, like murine macrophages, also release increased amounts of LAF when incubated with GL(1). The effect of GL(1) was dose-responsive and synergy was found with lipopolysaccharide. The relevance of these findings to the pathogenesis of Gaucher's disease is considered.