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-连环蛋白能够在不同类型的树突状细胞（DC）中诱导耐受性/抗炎性特征。单核细胞衍生的树突状细胞（moDC）已被广泛用于基于树突状细胞的癌症治疗，但迄今为止其临床疗效有限。我们想研究一个假设，即在moDCs中异常分化或双重促炎和抗炎特征的诱导可能是β-catenin依赖性的。在未成熟和脂多糖（LPS）刺激的DC中均可检测到β-catenin。β-catenin抑制剂ICG-001剂量依赖性地增加了促炎信号细胞因子IL-12p70，并降低了消炎信号分子IL-10。β-catenin激活剂6-溴二异丁星-3'-肟（6-BIO）剂量依赖性地增加了总的β-catenin和核中的β-catenin，这与IL-12p70降低，IL-10升高，活化标志物（如CD80和CD86）的表面表达降低以及抑制标志物（如PD-L1）的表达升高相关。关于这些功能，6-BIO和ICG-001的剂量依赖性竞争。全基因组的mRNA表达分析进一步强调了LPS成熟的moDC的促发和抗炎功能的双重发展，并暗示了β-catenin抑制在更有效的治疗性moDC产生中的作用。