Libby P, Sukhova G, Lee R T, Galis Z S
Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02115, USA.
J Cardiovasc Pharmacol. 1995;25 Suppl 2:S9-12. doi: 10.1097/00005344-199500252-00003.
The cytokines are multipotent mediators of inflammation and immunity that can affect key functions of vascular wall cells. Growing evidence suggests that cytokines participate as autocrine or paracrine mediators in atherogenesis, as cells in lesions can both produce and respond to these mediators. The functions of vascular wall cells regulated by cytokines may influence lesion initiation, progression, or complication. For example, cytokines can regulate the expression of adhesion molecules crucial to the recruitment of leukocytes to lesions, including vascular cell adhesion molecule-1 (VCAM-1). Cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) can regulate the production of monocyte chemoattractant protein-1 (MCP-1), a potential signal for directed migration of monocytes into the intima. Cytokines can also regulate genes that encode other growth factors and cytokines themselves. TNF-alpha can induce IL-1 mRNA in human endothelial (EC) and smooth-muscle cells (SMC). IL-1 and TNF-alpha can augment the production by vascular cells of macrophage-colony stimulating factor (M-CSF), which may promote growth and activation of mononuclear phagocytes. Cytokines can exert both pro-and antiatherogenic actions. Activated T cells in human atheroma may secrete the lymphokine IFN-gamma, an inhibitor of SMC proliferation. Cytokines influence vasomotor tone in arteries, e.g., by inducing a form of nitric oxide synthase, the enzyme that synthesizes the vasodilatory nitric oxide radical. The cytokines also modulate endothelial functions that govern the formation and stability of blood thrombi. Finally, in the late stages of the disease, matrix metalloproteinases derived from macrophages or smooth-muscle cells themselves may contribute to weakening of the fibrous cap in the vulnerable shoulder area, promoting plaque rupture and occlusive thrombosis, culminating in the dramatic clinical manifestations of atherosclerosis, including myocardial infarction and stroke. Thus, cytokines can influence multiple aspects of atherogenesis and provide new and interesting targets for therapeutic intervention.
细胞因子是炎症和免疫的多效性介质，可影响血管壁细胞的关键功能。越来越多的证据表明，细胞因子作为自分泌或旁分泌介质参与动脉粥样硬化的发生，因为病变中的细胞既能产生这些介质，又能对其作出反应。细胞因子调节的血管壁细胞功能可能会影响病变的起始、进展或并发症。例如，细胞因子可调节对白细胞募集到病变至关重要的黏附分子的表达，包括血管细胞黏附分子-1（VCAM-1）。白细胞介素-1（IL-1）和肿瘤坏死因子-α（TNF-α）等细胞因子可调节单核细胞趋化蛋白-1（MCP-1）的产生，MCP-1是单核细胞定向迁移到内膜的潜在信号。细胞因子还可调节编码其他生长因子和细胞因子自身的基因。TNF-α可在人内皮细胞（EC）和平滑肌细胞（SMC）中诱导IL-1 mRNA。IL-1和TNF-α可增加血管细胞对巨噬细胞集落刺激因子（M-CSF）的产生，这可能促进单核吞噬细胞的生长和活化。细胞因子可发挥促动脉粥样硬化和抗动脉粥样硬化作用。人动脉粥样硬化病变中活化的T细胞可能分泌淋巴因子干扰素-γ，这是一种SMC增殖抑制剂。细胞因子影响动脉的血管舒缩张力，例如，通过诱导一种一氧化氮合酶，该酶可合成血管舒张性一氧化氮自由基。细胞因子还调节控制血栓形成和稳定性的内皮功能。最后，在疾病后期，源自巨噬细胞或平滑肌细胞自身的基质金属蛋白酶可能导致易损肩部区域纤维帽的弱化，促进斑块破裂和闭塞性血栓形成，最终导致动脉粥样硬化的显著临床表现，包括心肌梗死和中风。因此，细胞因子可影响动脉粥样硬化发生的多个方面，并为治疗干预提供新的有趣靶点。
