Laboratory of Experimental Cardiology, University Medical Centre Utrecht, Utrecht, The Netherlands.
Clin Sci (Lond). 2012 Jun;122(11):527-33. doi: 10.1042/CS20110323.
TLR (Toll-like receptor) activation-induced inflammatory responses are important in the progression of atherosclerosis. We previously showed that TLR-dependent leucocyte responsiveness is acutely attenuated following percutaneous coronary intervention or vascular surgery. Furthermore, cytokine release following whole-blood TLR-2 and TLR-4 stimulation is negatively correlated with fractional flow reserve, suggesting that chronic ischaemia can elicit an enhanced inflammatory response. In the present study, we assessed the association between leucocyte TLR-2 and TLR-4 responsiveness and pre-existent and inducible ischaemia in patients undergoing SPECT (single-photon emission computed tomography)-MPI (myocardial perfusion imaging). TLR-2, TLR-4 and CD11b expression on monocytes were measured in blood samples that were obtained from 100 patients with suspected coronary artery disease before and after myocardial stress testing for SPECT-MPI. IL-8 (interleukin-8) levels were determined after whole-blood stimulation with Pam3Cys (TLR-2) and LPS (lipopolysaccharide; TLR-4). On the basis of SPECT-MPI, patients were categorized into three groups: reversible defect, irreversible defect and no defect. Myocardial stress induced a reduction in TLR-4 expression (2.46±0.21 compared with 2.17±0.16 arbitrary units, P=0.001) and CD11b expression (83.2±1.73 compared with 76.0±1.89 arbitrary units, P<0.001). TLR-induced IL-8 production before myocardial stress induction was not associated with the results of SPECT-MPI. However, a significant decrease in IL-8 production following TLR stimulation was observed after stress, which was more pronounced in patients with a reversible defect. In conclusion, inducible ischaemia is associated with a decrease in whole-blood TLR-2 and TLR-4 response. These results point to a regulating role of TLRs in order to prevent excessive inflammatory events known to occur during acute ischaemia.
TLR（Toll 样受体）激活诱导的炎症反应在动脉粥样硬化的进展中很重要。我们之前已经表明，经皮冠状动脉介入治疗或血管手术后，TLR 依赖性白细胞反应性会急性减弱。此外，全血 TLR-2 和 TLR-4 刺激后的细胞因子释放与血流储备分数呈负相关，这表明慢性缺血可引起增强的炎症反应。在本研究中，我们评估了白细胞 TLR-2 和 TLR-4 反应性与接受 SPECT（单光子发射计算机断层扫描）-MPI（心肌灌注成像）的患者中预先存在和可诱导的缺血之间的相关性。在进行 SPECT-MPI 心肌应激试验之前和之后，从 100 例疑似冠心病患者的血液样本中测量单核细胞上的 TLR-2、TLR-4 和 CD11b 的表达。在用 Pam3Cys（TLR-2）和 LPS（脂多糖；TLR-4）刺激全血后，测定 IL-8（白细胞介素-8）水平。根据 SPECT-MPI，患者被分为三组：可逆性缺陷、不可逆性缺陷和无缺陷。心肌应激导致 TLR-4 表达减少（2.46±0.21 与 2.17±0.16 任意单位，P=0.001）和 CD11b 表达减少（83.2±1.73 与 76.0±1.89 任意单位，P<0.001）。心肌应激诱导前 TLR 诱导的 IL-8 产生与 SPECT-MPI 的结果无关。然而，在应激后观察到 TLR 刺激后 IL-8 产生的显著减少，在具有可逆性缺陷的患者中更为明显。总之，可诱导的缺血与全血 TLR-2 和 TLR-4 反应的减少有关。这些结果表明 TLR 在急性缺血期间已知发生的过度炎症事件中发挥调节作用。
