SELECTIVE EFFECTS OF GLUCOCEREBROSIDE (GAUCHERS STORAGE MATERIAL) ON MACROPHAGE CULTURES
SELECTIVE EFFECTS OF GLUCOCEREBROSIDE (GAUCHERS STORAGE MATERIAL) ON MACROPHAGE CULTURES
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DOI：
10.1172/jci110363
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发表时间：
1981-01-01
影响因子：
15.9
通讯作者：
BARRANGER, JA
中科院分区：
文献类型：
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作者：
GERY, I;ZIGLER, JS;BARRANGER, JA
虽然戈谢病的酶损害是公认的，但对涉及该疾病临床表现的致病机制知之甚少。为了深入了解戈谢病的这一未探索的方面，在培养的小鼠巨噬细胞单层中在细胞水平上检查了葡糖脑苷脂（GL 1）的作用。向这些培养物中加入GL 1刺激巨噬细胞向培养基中释放增加量的淋巴细胞活化因子（LAF）和溶酶体酶。这些反应与添加到培养物中的GL 1的量成比例。在更高水平的GL 1（≥10 μ g/ml），乳酸脱氢酶（一种细胞质酶）也被释放，表明在这些剂量下细胞损伤。细胞内LAF在与高剂量GL 1孵育的巨噬细胞中也增加，表明这些细胞的总LAF产生增加。脂多糖与GL 1协同作用，并刺激释放极高水平的LAF，其具有与单独暴露于脂多糖释放的LAF相似的MW分布。与GL 1不同，半乳糖苷、鞘磷脂和神经酰胺三己糖苷对巨噬细胞产物的释放几乎没有影响。GL 1的作用对巨噬细胞具有选择性，因为将该材料加入小鼠透镜上皮细胞中未检测到细胞毒性作用，并且在巨噬细胞明显受影响的浓度下，仅对[脾、胸腺]淋巴细胞或[小鼠肥大细胞瘤] P815细胞具有轻微毒性。观察到鞘脂的细胞毒性与其在各种细胞中的累积之间存在直接关系。巨噬细胞积累了大量的GL 1，但没有鞘磷脂;在这项研究中检查的其他细胞没有积累这些脂质。与鼠巨噬细胞一样，人单核细胞在与GL 1孵育时也释放增加量的LAF。GL 1的作用是剂量反应性的，并与脂多糖有协同作用。这些发现的相关性戈谢病的发病机制被认为是。
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, the effects of glucocerebroside (GL1) were examined 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 (.gtoreq. 10 .mu.g/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 MW 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 GL1 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 [spleen, thymus] lymphocytes or [mouse mastocytoma] 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 GL1 but not sphingomyelin; 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 GL1. The effect of GL1 was dose-responsive and synergy was found with lipopolysaccharide. The relevance of these findings to the pathogenesis of Gaucher''s disease is considered.