Interferon-γ elicits arteriosclerosis in the absence of leukocytes
Interferon-γ elicits arteriosclerosis in the absence of leukocytes
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DOI：
10.1038/35003221
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发表时间：
2000-01-13
期刊：
影响因子：
64.8
通讯作者：
Pober, JS
中科院分区：
文献类型：
--
作者：
Tellides, G;Tereb, DA;Pober, JS
动脉粥样硬化和移植后移植物动脉粥样硬化的特征都是由于单核白细胞的浸润、血管平滑肌细胞（VSMC）的增殖和细胞外基质的积累导致的动脉内膜的扩张（1-3）。它们还与免疫调节细胞因子干扰素-γ（IFN-γ）的存在有关（2，3）。此外，在动脉粥样硬化形成或同种异体移植的小鼠模型中，IFN-γ的血清学中和（4）或遗传缺失（5-8）显著降低内膜扩张的程度。然而，其他研究发现外源性IFN-γ抑制培养的VSMC增殖（9-14）和基质合成（15），并减少响应于机械损伤的内膜扩张（16-18）。这种差异通常可以用以下观点来解释：IFN-γ直接激活巨噬细胞，或者通过增加抗原呈递，间接激活动脉粥样硬化和移植物动脉硬化病变内的T细胞。这些活化的白细胞被认为表达VSMC活化细胞因子（1-3）和细胞表面分子（19），导致观察到的动脉炎反应。在这里，我们将猪和人的动脉插入免疫缺陷小鼠的主动脉中，我们表明，在缺乏可检测到的免疫细胞的情况下，IFN-γ可以通过作用于VSMC来增强生长因子诱导的有丝分裂来诱导动脉硬化变化。
Atherosclerosis and post-transplant graft arteriosclerosis are both characterized by expansion of the arterial intima as a result of the infiltration of mononuclear leukocytes, the proliferation of vascular smooth muscle cells (VSMCs) and the accumulation of extracellular matrix(1-3). They are also associated with the presence of the immunomodulatory cytokine interferon-gamma (IFN-gamma)(2,3). Moreover, in mouse models of atheroma formation or allogeneic transplantation, the serological neutralization(4) or genetic absence(5-8) of IFN-gamma markedly reduces the extent of intimal expansion. However, other studies have found that exogenous IFN-gamma inhibits Cultured VSMC proliferation(9-14) and matrix synthesis(15), and reduces intimal expansion in response to mechanical injury(16-18). This discrepancy is generally explained by the idea that IFN-gamma either directly activates macrophages, or, by increasing antigen presentation, indirectly activates T cells within the lesions of atherosclerosis and graft arteriosclerosis. These activated leukocytes are thought to express the VSMC-activating cytokines(1-3) and cell-surface molecules(19) that cause the observed arteriosclerotic responses. Here we have inserted pig and human arteries into the aorta of immunodeficient immunodeficient mice, and we show that IFN-gamma can induce arteriosclerotic changes in the absence of detectable immunocytes by acting on VSMCs to potentiate growth-factor-induced mitogenesis.