Modulation of human monocyte/macrophage activity by tocilizumab, abatacept and etanercept: An in vitro study
Modulation of human monocyte/macrophage activity by tocilizumab, abatacept and etanercept: An in vitro study
复制标题
DOI：
10.1016/j.ejphar.2016.03.028
复制
发表时间：
2016-06-05
影响因子：
5
通讯作者：
Fresu, Luigia Grazia
中科院分区：
文献类型：
--
作者：
Obeng, Joyce Afrakoma;Amoruso, Angela;Fresu, Luigia Grazia
托珠单抗、依那西普和阿巴接受是用于治疗类风湿性关节炎（RA）的生物药物。其作用机制已被充分证明，但其对人类单核细胞/巨噬细胞的直接影响尚未被充分研究。本研究的目的是在体外评估这些药物对健康志愿者单核/巨噬细胞的影响。从健康的匿名志愿者中分离出人类单核细胞，并进行培养或分化为单核细胞来源的巨噬细胞（MDMs）。评估托珠单抗、依那西普和阿巴接受（浓度与患者血浆相似）对超氧阴离子产生、基质金属蛋白酶-9 （MMP-9）基因表达和活性、过氧化物酶体增殖物激活受体(PPAR) γ表达和细胞表型的影响。单核/巨噬细胞暴露于托珠单抗、依那西普或阿巴接受可显著降低pma诱导的超氧阴离子产生。有趣的是，PPAR γ的表达只有托珠单抗才能显著增加，而依那西普是唯一一种能够显著降低MMP-9基因表达并抑制lps诱导的单核细胞MMP-9活性的药物。当分化培养基中加入依那西普和阿巴接受时，两者均显著减少wCD206(+)MDM数量。本研究表明依那西普、阿巴接受和托珠单抗对人单核/巨噬细胞的影响不同。特别是，IL-6拮抗剂tocilizumab在诱导单核细胞/巨噬细胞的抗炎表型方面似乎比依那西普和阿巴接受更有效，这也是由于PPAR γ的上调，其抗炎作用已得到充分认识。(C) 2016 Elsevier B.V.版权所有
Tocilizumab, etanercept and abatacept are biological drugs used in the therapy of Rheumatoid Arthritis (RA). Their mechanism of action is well documented but their direct effects on human monocytes/macrophages have not been fully investigated. The objective of this study was to evaluate in vitro the influence of these drugs on monocytes/macrophages from healthy volunteers.Human monocytes were isolated from healthy anonymous volunteers and cultured as such or differentiated to monocyte-derived macrophages (MDMs). The effect of tocilizumab, etanercept and abatacept (at concentrations similar to those in plasma of patients) on superoxide anion production, matrix metalloproteinase-9 (MMP-9) gene expression and activity, Peroxisome Proliferator-Activated Receptor (PPAR)gamma expression and cell phenotype was evaluated.Exposure of monocytes/macrophages to tocilizumab, etanercept or abatacept resulted in a significant decrease of the PMA-induced superoxide anion production. Interestingly, the expression of PPAR gamma was significantly increased only by tocilizumab, while etanercept was the only one able to significantly reduce MMP-9 gene expression and inhibit the LPS-induced MMP-9 activity in monocytes. When etanercept and abatacept were added to the differentiating medium, both significantly reduced the amount of wCD206(+)MDM.This study demonstrates that etanercept, abatacept and tocilizumab affect differently human monocytes/macrophages. In particular, the IL-6 antagonist tocilizumab seems to be more effective in inducing an anti-inflammatory phenotype of monocytes/macrophages compared to etanercept and abatacept, also in light of the up-regulation of PPAR gamma whose anti-inflammatory effects are well recognised. (C) 2016 Elsevier B.V. All rights reserved.