IL-6 blockade by monoclonal antibodies inhibits apolipoprotein (a) expression and lipoprotein (a) synthesis in humans[S]
IL-6 blockade by monoclonal antibodies inhibits apolipoprotein (a) expression and lipoprotein (a) synthesis in humans[S]
复制标题
单克隆抗体阻断 IL-6 可抑制人类载脂蛋白 (a) 表达和脂蛋白 (a) 合成[S]
作者：
N. Müller;D. Schulte;K. Türk;S. Freitag;J. Hampe;R. Zeuner;J. Schröder;I. Gouni;H. Berthold;W. Krone;S. Rose;S. Schreiber;M. Laudes
脂蛋白（a）[Lp（a）]是一种高度致动脉粥样硬化的脂质颗粒。虽然早期的报道表明Lp（a）水平主要由遗传因素决定，但最近的几项研究表明，Lp（a）诱导也是由慢性炎症引起的。因此，我们的目的是检查单克隆抗体的细胞因子阻断是否可以抑制Lp（a）代谢。我们发现，托珠单抗（TCZ）阻断白细胞介素6（IL-6）可降低Lp（a），而阿达木单抗抑制TNF-α则无影响。IL-6在调节Lp（a）中的特异性通过人类受试者（n = 1，153）的血清学测量进一步证明，其揭示在血清IL-6升高的个体中Lp（a）水平升高。对人肝活检组织（n = 57）的转录组学分析揭示了典型的IL-6应答基因与体内LPA基因表达相关。在分子水平上，我们发现TCZ抑制IL-6诱导的人肝细胞LPA mRNA和蛋白的表达。此外，通过报告基因分析、启动子缺失实验和电泳迁移率变动分析对LPA启动子内IL-6应答信号转导子和转录激活子3结合位点的检测表明，TCZ降低Lp（a）的作用是通过-46至-40的应答元件特异性介导的。因此，IL-6阻断可能是治疗人类血清Lp（a）浓度升高的潜在治疗选择，并且可能是未来脂质分离的非侵入性替代方案。
Lipoprotein (a) [Lp(a)] is a highly atherogenic lipid particle. Although earlier reports suggested that Lp(a) levels are mostly determined by genetic factors, several recent studies have revealed that Lp(a) induction is also caused by chronic inflammation. Therefore, we aimed to examine whether cytokine blockade by monoclonal antibodies may inhibit Lp(a) metabolism. We found that interleukin 6 (IL-6) blockade by tocilizumab (TCZ) reduced Lp(a) while TNF-α-inhibition by adalimumab in humans had no effect. The specificity of IL-6 in regulating Lp(a) was further demonstrated by serological measurements of human subjects (n = 1,153) revealing that Lp(a) levels are increased in individuals with elevated serum IL-6. Transcriptomic analysis of human liver biopsies (n = 57) revealed typical IL-6 response genes being correlated with the LPA gene expression in vivo. On a molecular level, we found that TCZ inhibited IL-6-induced LPA mRNA and protein expression in human hepatocytes. Furthermore, examination of IL-6-responsive signal transducer and activator of transcription 3 binding sites within the LPA promoter by reporter gene assays, promoter deletion experiments, and electrophoretic mobility shift assay analysis showed that the Lp(a)-lowering effect of TCZ is specifically mediated via a responsive element at −46 to −40. Therefore, IL-6 blockade might be a potential therapeutic option to treat elevated Lp(a) serum concentrations in humans and might be a noninvasive alternative to lipid apheresis in the future.
影响因子：
15.9
作者：
BOERWINKLE, E;LEFFERT, CC;HOBBS, HH
通讯作者：
HOBBS, HH
影响因子：
37.8
作者：
M. Espeland;S. Marcovina;Valery T. Miller;Peter D. Wood;C. Wasilauskas;Roger Sherwin;Helmut G. Schrott;T. Bush
通讯作者：
M. Espeland;S. Marcovina;Valery T. Miller;Peter D. Wood;C. Wasilauskas;Roger Sherwin;Helmut G. Schrott;T. Bush