Waehre Torgun, Yndestad Arne, Smith Camilla, Haug Terje, Tunheim Siv Haugen, Gullestad Lars, Frøland Stig S, Semb Anne G, Aukrust Pål, Damås Jan K
Research Institute of Internal Medicine, Rikshospitalet, N-0027 Oslo, Norway.
Circulation. 2004 Apr 27;109(16):1966-72. doi: 10.1161/01.CIR.0000125700.33637.B1. Epub 2004 Mar 29.
Inflammation is important in atherogenesis. Interleukin (IL)-1 is the prototypic inflammatory cytokine. We hypothesized a dysbalance between inflammatory and anti-inflammatory mediators in the IL-1 family in coronary artery disease (CAD) and a possible modulation of these mediators by HMG-CoA inhibitors (statins).
In a microarray screening experiment examining peripheral blood mononuclear cells (PBMCs) from 6 CAD patients and 4 healthy control subjects, IL-1beta was identified as 1 of 25 genes whose expression were upregulated in CAD and downregulated by statins. In the following, we studied the role of IL-1beta and related mediators in CAD. Our major findings were as follows. (1) Although mRNA levels of IL-1alpha and IL-1beta were markedly reduced in PBMCs from CAD patients after 6 months of simvastatin (20 mg/d, n=15) and atorvastatin (80 mg/d, n=15) therapy, the reduction in IL-1 receptor antagonist (IL-1Ra) was more modest. Statins also reduced the spontaneous release of IL-1beta and IL-1Ra from PBMCs in CAD patients. (2) mRNA levels of IL-1alpha, IL-1beta, and IL-1Ra were increased in PBMCs from patients with stable (n=20) and unstable (n=20) angina compared with healthy control subjects (n=15). Although the unstable patients had particularly high levels of IL-1beta and IL-1alpha, IL-1Ra was not correspondingly increased. (3) IL-1beta induced release of proatherogenic cytokines from PBMCs, whereas atorvastatin partly abolished this effect.
Our findings suggest that cytokines in the IL-1 family may represent therapeutic targets in CAD. The ability of statins to modulate these cytokines in an anti-inflammatory direction underscores their immunomodulatory potential.
炎症在动脉粥样硬化形成过程中起重要作用。白细胞介素（IL）-1是典型的炎性细胞因子。我们推测在冠状动脉疾病（CAD）中，IL-1家族的炎性介质与抗炎介质之间存在失衡，且3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）抑制剂（他汀类药物）可能对这些介质具有调节作用。
在一项微阵列筛选实验中，检测了6例CAD患者和4例健康对照者的外周血单个核细胞（PBMC），IL-1β被确定为CAD中表达上调且被他汀类药物下调的25个基因之一。接下来，我们研究了IL-1β及相关介质在CAD中的作用。我们的主要发现如下：（1）辛伐他汀（20mg/d，n = 15）和阿托伐他汀（80mg/d，n = 15）治疗6个月后，CAD患者PBMC中IL-1α和IL-1β的mRNA水平显著降低，但IL-1受体拮抗剂（IL-1Ra）的降低幅度较小。他汀类药物还减少了CAD患者PBMC中IL-1β和IL-1Ra的自发释放。（2）与健康对照者（n = 15）相比，稳定型（n = 20）和不稳定型（n = 20）心绞痛患者的PBMC中IL-1α、IL-1β和IL-1Ra的mRNA水平升高。尽管不稳定型患者的IL-1β和IL-1α水平特别高，但IL-1Ra并未相应增加。（3）IL-1β诱导PBMC释放促动脉粥样硬化细胞因子，而阿托伐他汀部分消除了这种作用。
我们的研究结果表明，IL-1家族中的细胞因子可能是CAD的治疗靶点。他汀类药物在抗炎方向调节这些细胞因子的能力凸显了其免疫调节潜力。
