Monoclonal antibodies targeting IL-1 beta reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in Apolipoprotein E-deficient mice
Monoclonal antibodies targeting IL-1 beta reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in Apolipoprotein E-deficient mice
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DOI：
10.1016/j.atherosclerosis.2011.02.026
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发表时间：
2011-06-01
期刊：
影响因子：
5.3
通讯作者：
Kantak, Seema S.
中科院分区：
文献类型：
--
作者：
Bhaskar, Vinay;Yin, Johnny;Kantak, Seema S.
目的：动脉粥样硬化是一种通过并发症（如中风和心肌梗死）导致全球死亡率日益增加的疾病。IL-1 β通过诱导巨噬细胞、内皮细胞（EC）和平滑肌细胞（SMC）产生额外的细胞因子和蛋白水解酶，在动脉粥样硬化的形成和稳定性中发挥多种直接的局部作用。因此，我们测试了抗IL-1 β抗体XOMA 052是否可以抑制巨噬细胞在体外分泌促动脉粥样硬化细胞因子，并影响载脂蛋白E缺陷小鼠的阳性结果体内动脉粥样硬化的ApoE（-/-）模型。在体外共培养模型中，XOMA 052抑制巨噬细胞诱导的EC和SMC分泌关键致动脉粥样硬化细胞因子，包括IL-6，IL-8，MCP-1和TNF α。XOMA 052还降低了降解酶如基质金属蛋白酶MMP-3和MMP-9的释放。此外，XOMA 052抑制EC分泌IL-7和SMC分泌IL-4，这些细胞因子以前没有报道在这种情况下由IL-1 β驱动。在体内，XMA 052 MG 1 K（XOMA 052的嵌合鼠版本）在所有三种测试剂量下均抑制ApoE（-/-）模型中动脉粥样硬化病变的形成。该效应与报道的在ApoE（-/-）背景下完全基因消融IL-1 β或IL-1 R1的效应相当，并且与血浆非HDL/HDL胆固醇比率和斑块脂质含量以及巨噬细胞浸润的降低相关。这些结果首次证明靶向IL-1 β的抗体可以在体内抑制动脉粥样硬化的进展，强调了这种关键细胞因子在心血管疾病中的重要性。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
Objective: Atherosclerosis is a condition that is increasingly contributing to worldwide mortality through complications such as stroke and myocardial infarction. IL-1 beta plays multiple direct, local roles in the formation and stability of the atheroma by eliciting the production of additional cytokines and proteolytic enzymes from macrophages, endothelial cells (EC) and smooth muscle cells (SMC). We therefore tested whether an anti-IL-1 beta antibody, XOMA052, might inhibit the secretion of pro-atherogenic cytokines from macrophages in vitro and affect a positive outcome in the Apolipoprotein E-deficient mouse (ApoE(-/-)) model of atherosclerosis in vivo.Methods and results: In an in vitro co-culture model, XOMA 052 inhibited macrophage-induced secretion of key atherogenic cytokines from EC and SMC, including IL-6, IL-8, MCP-1 and TNF alpha. The release of degradative enzymes, such as the matrix metalloproteinases MMP-3 and MMP-9, was also decreased by XOMA 052. In addition, XOMA 052 inhibited the secretion of IL-7 from EC and IL-4 from SMC, cytokines not previously reported to be driven by IL-1 beta in this context. In vivo, XMA052 MG1K, a chimeric murine version of XOMA 052, inhibited the formation of atherosclerotic lesions in the ApoE(-/-) model at all three doses tested. This effect was comparable to that reported for complete genetic ablation of IL-1 beta or IL-1R1 on an ApoE(-/-) background and was associated with decreases in plasma non-HDL/HDL cholesterol ratio and plaque lipid content and macrophage infiltration.Conclusions: These results demonstrate for the first time that an antibody targeting IL-1 beta can inhibit the progression of atherosclerosis in vivo, highlighting the importance of this key cytokine in cardiovascular disease. (C) 2011 Elsevier Ireland Ltd. All rights reserved.