Selective Effects of Glucocerebroside (Gaucher's Storage Material) on Macrophage Cultures

Abstract

A B S T R A C T Although the enzymatic lesion inGaucher'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 (GL1) at the cellular level in monolayers of cultured murine macrophages. The addition of GL1 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 GL1 added to the culture. At higher levels of GL1 (.20 ,ug/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 GL1, demonstrating an increase in total LAF production by these cells. Lipopolysaccharide acted synergistically with GL1 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 GL1, galactocerebroside, sphingomyelin, and ceramidetrihexoside, exerted little or no effect on the release of macrophage products. The effect of GL, 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 accumu-

Coagulation abnormalities in type 1 Gaucher disease are due to low‐grade activation and can be partly restored by enzyme supplementation therapy

“…In addition, several cytokines, including TNF, have proven to induce activation of coagulation and fibrinolysis (van der Poll et al, 1990(van der Poll et al, , 1991. In vitro observations have suggested a role for IL1 in the pathophysiology of Gaucher disease (Gery et al, 1981). We did not find elevated TNF and IL6 levels in serum of type 1 Gaucher disease patients (unpublished data); however, increased local production can not be excluded.…”

Differential Effects of Enzyme Supplementation Therapy on Manifestations of Type 1 Gaucher Disease

“…In line with this hypothesis of activation of Gaucher cells is the observation that glucocerebroside stimulates lipopolysaccharide-stimulated interleukin-1 production by murine macrophages. 34 In our previous study we have shown that REE is increased in the GD patients by Ç30% compared with healthy controls. 3 This is confirmed by a larger series of patients in the present study.…”

Elevated Levels of M-CSF, sCD14 and IL8 in Type 1 Gaucher Disease

“…The correlation of M-CSF, sCD14 and IL8 levels with disease manifestations suggests this. Further support is found in the fact that in vitro activation with LPS of murine macrophages, pre-incubated with glucosylceramide, are capable of enhanced IL1 production (8). However, it should be stressed that sCD14 can also be released by monocytes and IL8 and M-CSF can be produced by many other cell-types.…”

“…A role for cytokines in the pathophysiology of the disease has been suggested previously (1,3,7). Indeed, in vitro stimulation of murine macrophages with glucosylceramide has revealed enhanced production of IL1 (8). Recently, elevated plasma levels of TNFa were reported in some patients with Gaucher disease (9).…”