Wong M L, Xie B, Beatini N, Phu P, Marathe S, Johns A, Gold P W, Hirsch E, Williams K J, Licinio J, Tabas I
Department of Psychiatry and Biobehavioral Sciences, University of California, School of Medicine, Los Angeles, CA 90095-1761, USA.
Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8681-6. doi: 10.1073/pnas.150098097.
Inflammation plays a critical role in atherogenesis, yet the mediators linking inflammation to specific atherogenic processes remain to be elucidated. One such mediator may be secretory sphingomyelinase (S-SMase), a product of the acid sphingomyelinase gene. The secretion of S-SMase by cultured endothelial cells is induced by inflammatory cytokines, and in vivo data have implicated S-SMase in subendothelial lipoprotein aggregation, macrophage foam cell formation, and possibly other atherogenic processes. Thus, the goal of this study was to seek evidence for S-SMase regulation in vivo during a physiologically relevant inflammatory response. First, wild-type mice were injected with saline or lipopolysaccharide (LPS) as a model of acute systemic inflammation. Serum S-SMase activity 3 h postinjection was increased 2- to 2.5-fold by LPS (P < 0.01). To determine the role of IL-1 in the LPS response, we used IL-1 converting enzyme knockout mice, which exhibit deficient IL-1 bioactivity. The level of serum S-SMase activity in LPS-injected IL-1 converting enzyme knockout mice was approximately 35% less than that in identically treated wild-type mice (P < 0.01). In LPS-injected IL-1-receptor antagonist knockout mice, which have an enhanced response to IL-1, serum S-SMase activity was increased 1. 8-fold compared with LPS-injected wild-type mice (P < 0.01). Finally, when wild-type mice were injected directly with IL-1beta, tumor necrosis factor alpha, or both, serum S-SMase activity increased 1. 6-, 2.3-, and 2.9-fold, respectively (P < 0.01). These data show regulation of S-SMase activity in vivo and they raise the possibility that local stimulation of S-SMase may contribute to the effects of inflammatory cytokines in atherosclerosis.
炎症在动脉粥样硬化形成过程中起关键作用，然而，将炎症与特定动脉粥样硬化形成过程联系起来的介质仍有待阐明。一种这样的介质可能是分泌型鞘磷脂酶（S-SMase），它是酸性鞘磷脂酶基因的产物。培养的内皮细胞分泌S-SMase是由炎性细胞因子诱导的，体内数据表明S-SMase参与内皮下脂蛋白聚集、巨噬细胞泡沫细胞形成以及可能的其他动脉粥样硬化形成过程。因此，本研究的目的是寻找在生理相关的炎症反应过程中体内S-SMase调节的证据。首先，将野生型小鼠注射生理盐水或脂多糖（LPS）作为急性全身炎症模型。注射后3小时，LPS使血清S-SMase活性增加2至2.5倍（P<0.01）。为了确定IL-1在LPS反应中的作用，我们使用了IL-1转换酶基因敲除小鼠，这些小鼠表现出IL-1生物活性缺陷。注射LPS的IL-1转换酶基因敲除小鼠的血清S-SMase活性水平比相同处理的野生型小鼠低约35%（P<0.01）。在注射LPS的IL-1受体拮抗剂基因敲除小鼠中，这些小鼠对IL-1的反应增强，与注射LPS的野生型小鼠相比，血清S-SMase活性增加了1.8倍（P<0.01）。最后，当直接给野生型小鼠注射IL-1β、肿瘤坏死因子α或两者时，血清S-SMase活性分别增加了1.6倍、2.3倍和2.9倍（P<0.01）。这些数据表明体内S-SMase活性受到调节，并且它们增加了局部刺激S-SMase可能促成炎性细胞因子在动脉粥样硬化中的作用的可能性。
