Department of Microbiology, Haukeland University Hospital, Helse Bergen, Bergen, Norway.
Department of Clinical Science, University of Bergen, Bergen, Norway.
Front Immunol. 2020 Mar 27;11:438. doi: 10.3389/fimmu.2020.00438. eCollection 2020.
The transcription factor β-catenin is able to induce tolerogenic/anti-inflammatory features in different types of dendritic cells (DCs). Monocyte-derived dendritic cells (moDCs) have been widely used in dendritic cell-based cancer therapy, but so far with limited clinical efficacy. We wanted to investigate the hypothesis that aberrant differentiation or induction of dual pro- and anti-inflammatory features may be β-catenin dependent in moDCs. β-catenin was detectable in both immature and lipopolysaccharide (LPS)-stimulated DCs. The β-catenin inhibitor ICG-001 dose-dependently increased the pro-inflammatory signature cytokine IL-12p70 and decreased the anti-inflammatory signature molecule IL-10. The β-catenin activator 6-bromoindirubin-3'-oxime (6-BIO) dose-dependently increased total and nuclear β-catenin, and this was associated with decreased IL-12p70, increased IL-10, and reduced surface expression of activation markers, such as CD80 and CD86, and increased expression of inhibitory markers, such as PD-L1. 6-BIO and ICG-001 competed dose-dependently regarding these features. Genome-wide mRNA expression analyses further underscored the dual development of pro- and anti-inflammatory features of LPS-matured moDCs and suggest a role for β-catenin inhibition in production of more potent therapeutic moDCs.
转录因子β-连环蛋白能够诱导不同类型树突状细胞（DCs）产生耐受/抗炎特征。单核细胞来源的树突状细胞（moDCs）已广泛用于基于树突状细胞的癌症治疗，但迄今为止疗效有限。我们希望研究这样一种假设，即在 moDCs 中，异常分化或诱导双重促炎和抗炎特征可能依赖于β-连环蛋白。β-连环蛋白在未成熟和脂多糖（LPS）刺激的 DCs 中均可检测到。β-连环蛋白抑制剂 ICG-001 呈剂量依赖性增加促炎特征细胞因子 IL-12p70，并降低抗炎特征分子 IL-10。β-连环蛋白激活剂 6-溴靛红-3'-肟（6-BIO）呈剂量依赖性增加总核β-连环蛋白，这与 IL-12p70 减少、IL-10 增加以及激活标志物（如 CD80 和 CD86）表面表达减少和抑制标志物（如 PD-L1）表达增加相关。6-BIO 和 ICG-001 关于这些特征呈剂量依赖性竞争。全基因组 mRNA 表达分析进一步强调了 LPS 成熟 moDCs 中促炎和抗炎特征的双重发展，并表明β-连环蛋白抑制在产生更有效的治疗性 moDCs 方面发挥作用。
