Zuckerman S H, Evans G F, O'Neal L
Lilly Research Labs, Indianapolis, IN 46285.
Atherosclerosis. 1992 Oct;96(2-3):203-14. doi: 10.1016/0021-9150(92)90066-p.
Biosynthesis of apolipoprotein (apo) E has been previously demonstrated to be regulated in macrophages by intracellular free cholesterol levels as well as by macrophage activating factors. In this report, the regulation of apo E secretion by cytokines detected within atherosclerotic lesions has been investigated. Granulocyte macrophage-colony stimulating factor (GM-CSF) stimulated macrophages had a 3-5-fold reduction in apo E secretion, comparable to that observed for gamma interferon (IFN gamma), while tumor necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL-1 beta) resulted in a 2-fold decrease. In contrast to the reduction in apo E secretion by these cytokines, transforming growth factor beta (TGF-beta) stimulated macrophages secreted 3-fold greater amounts of apo E than controls. The reduced secretion of apo E by GM-CSF was reversible, heat labile, dose dependent, maximal 48 h after cytokine exposure and was coincident with an increase in fibronectin secretion. The opposing effects of GM-CSF and TGF-beta on apo E secretion were consistent with similar changes detected in apo E mRNA levels. Cytokine effects on apo E secretion in cholesterol loaded macrophages were also investigated and found to be similar to the non-loaded cells with GM-CSF decreasing and TGF-beta increasing apo E secretion. The observed differences in apo E secretion did not correlate with any significant changes in either cellular cholesterol distribution in the non-cholesterol loaded macrophages or in basal ACAT activity. In addition to changes in apo E secretion, cytokine treated macrophages pulsed with [14C]oleate and acetylated LDL for 2-6 h had a 2-fold increase (GM-CSF) or decrease (TGF-beta) in cholesterol esterification. Therefore, GM-CSF and TGF-beta mediated changes in apo E secretion may occur through a mechanism independent of changes in cellular free cholesterol levels. These results suggest that cytokines expressed within an atheroma may play an important role in the modulation of macrophage mediated reverse cholesterol transport.
先前已证明，载脂蛋白（apo）E的生物合成在巨噬细胞中受细胞内游离胆固醇水平以及巨噬细胞激活因子的调节。在本报告中，研究了动脉粥样硬化病变中检测到的细胞因子对apo E分泌的调节作用。粒细胞巨噬细胞集落刺激因子（GM-CSF）刺激的巨噬细胞apo E分泌减少了3至5倍，与γ干扰素（IFNγ）的情况相当，而肿瘤坏死因子α（TNFα）和白细胞介素1β（IL-1β）则导致其分泌减少2倍。与这些细胞因子导致apo E分泌减少相反，转化生长因子β（TGF-β）刺激的巨噬细胞分泌的apo E量比对照多3倍。GM-CSF导致的apo E分泌减少是可逆的、热不稳定的、剂量依赖性的，在细胞因子暴露后48小时达到最大值，并且与纤连蛋白分泌增加同时发生。GM-CSF和TGF-β对apo E分泌的相反作用与apo E mRNA水平检测到的类似变化一致。还研究了细胞因子对胆固醇负载巨噬细胞中apo E分泌的影响，发现与未负载细胞相似，GM-CSF降低而TGF-β增加apo E分泌。观察到的apo E分泌差异与未负载胆固醇的巨噬细胞中细胞胆固醇分布或基础ACAT活性的任何显著变化均无相关性。除了apo E分泌的变化外，用[14C]油酸酯和乙酰化低密度脂蛋白脉冲处理2至6小时的细胞因子处理巨噬细胞，其胆固醇酯化增加了2倍（GM-CSF）或减少（TGF-β）。因此，GM-CSF和TGF-β介导的apo E分泌变化可能通过独立于细胞游离胆固醇水平变化的机制发生。这些结果表明，动脉粥样瘤中表达的细胞因子可能在调节巨噬细胞介导的逆向胆固醇转运中起重要作用。
