Ríos-Navarro Cesar, de Pablo Carmen, Collado-Diaz Víctor, Orden Samuel, Blas-Garcia Ana, Martínez-Cuesta María Ángeles, Esplugues Juan V, Alvarez Angeles
Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; FISABIO- Hospital Universitario Dr. Peset, Valencia, Spain.
Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
Eur J Pharmacol. 2015 Oct 15;765:355-65. doi: 10.1016/j.ejphar.2015.08.054. Epub 2015 Sep 4.
Enhanced leukocyte recruitment is an inflammatory process that occurs during early phases of the vascular dysfunction that characterises atherosclerosis. We evaluated the impact of anti-TNF-α (adalimumab, infliximab and etanercept) and anti-IL-12/23 (ustekinumab) on interactions between human leukocytes and endothelial cells in a flow chamber that reproduced in vivo conditions. Clinical concentrations of anti-TNF-α were evaluated on the leukocyte recruitment induced by a variety of endothelial (TNF-α, interleukin-1β, lymphotoxin-α and angiotensin-II) and leukocyte (PAF, IL-12 and IL-23) stimuli related to inflammation and atherosclerosis. Treatment with anti-TNF-α, even before or after establishing the inflammatory situation induced by TNF-α, diminished leukocyte-endothelial cell interactions induced by this stimuli. Our results also implicated adhesion molecules (ICAM-1, VCAM-1 and E-selectin) in the actions of anti-TNF-α in terms of leukocyte adhesion to endothelium. However, anti-TNF-α drugs did not influence the actions of interleukin-1β, but prevented those of lymphotoxin-α and angiotensin-II. However, once established, inflammatory response elicited by the latter three stimuli could not be reversed. Pre-treatment with anti-TNF-α, also prevented leukocyte actions induced by IL-23 on PBMC rolling flux and rolling velocity and by IL-12 on PMN adhesion. Ustekinumab exhibited a more discreet profile, having no effect on leukocyte recruitment induced by any of the endothelial stimuli, while blocking the effects of IL-23 on leukocyte activation and those of IL-12 on PMN adhesion and PAF on PBMC rolling velocity. These findings endorse the idea that biological anti-inflammatory drugs, in particular anti-TNF-α, have the capacity to influence cardiovascular risk accompanying psoriasis and rheumatoid arthritis by ameliorating vascular inflammation.
白细胞募集增强是一种炎症过程，发生在以动脉粥样硬化为特征的血管功能障碍的早期阶段。我们在模拟体内条件的流动腔室中评估了抗TNF-α（阿达木单抗、英夫利昔单抗和依那西普）和抗IL-12/23（乌司奴单抗）对人白细胞与内皮细胞之间相互作用的影响。评估了抗TNF-α的临床浓度对由多种与炎症和动脉粥样硬化相关的内皮（TNF-α、白细胞介素-1β、淋巴毒素-α和血管紧张素-II）和白细胞（血小板活化因子、IL-12和IL-23）刺激物诱导的白细胞募集的影响。使用抗TNF-α治疗，即使在建立由TNF-α诱导的炎症状态之前或之后，也能减少由该刺激物诱导的白细胞-内皮细胞相互作用。我们的结果还表明，在白细胞与内皮细胞黏附方面，黏附分子（ICAM-1、VCAM-1和E-选择素）参与了抗TNF-α的作用。然而，抗TNF-α药物并不影响白细胞介素-1β的作用，但可阻止淋巴毒素-α和血管紧张素-II的作用。然而，一旦建立，后三种刺激物引发的炎症反应无法逆转。抗TNF-α预处理还可阻止IL-23对PBMC滚动通量和滚动速度以及IL-12对PMN黏附的诱导的白细胞作用。乌司奴单抗表现出更不明显的作用，对任何内皮刺激物诱导的白细胞募集均无影响，同时可阻断IL-23对白细胞活化的作用以及IL-12对PMN黏附的作用和血小板活化因子对PBMC滚动速度的作用。这些发现支持了这样一种观点，即生物抗炎药物，特别是抗TNF-α，能够通过改善血管炎症来影响银屑病和类风湿关节炎患者的心血管风险。
