Programmed death-ligand-1 (PD-L1) is a ligand for programmed death receptor (PD-1) that plays a major role in cell-mediated immune response; it regulates T-cell activation and regulates survival and functions of activated T cells. Expression of PD-L1 can induce chronic inflammation and activate mechanisms of immune evasion. PD-L1 is expressed in most of human carcinomas. Porphyromonas gingivalis (P. gingivalis) is a major keystone pathogen in periodontitis that invade host cells and disposes a variety of virulence factors. The aim of the present study was to clarify the signaling pathway of P. gingivalis molecules that induce PD-L1 up-regulation in colon carcinoma cells. Additionally, it was investigated which components of P. gingivalis are responsible for PD-L1 induction. Colon cancer cells (CL-11) were stimulated with total membrane (TM) fractions, peptidoglycans (PDGs) and viable P. gingivalis bacteria. Seven signaling molecule inhibitors were used: receptor-interacting serine/threonine-protein kinase 2 (RIP2) tyrosine kinase inhibitor, nucleotide-binding oligomerization domain (NOD)-like receptor 1&2 inhibitor, NOD-like receptor, nuclear factor kappa B inhibitor, c-Jun N-terminal kinases inhibitor, mitogen-activated protein/extracellular signal-regulated kinase inhibitor, mitogen activated kinase (MAPK) inhibitor. PD-L1 protein expression was examined by western blot analysis and quantitative real time PCR. It was demonstrated that the TM fraction and PDG induced up-regulation of PD-L1 expression in colon cancer cells. In conclusion, the results of this study suggest that PDG of P. gingivalis plays a major role in PD-L1 up-regulation in colon cancer cells. In addition, the mechanism of PD-L1 up-regulation depends on NOD 1 and NOD 2 and involves activation of RIP2 and MAPK signaling pathways.

中文翻译：

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牙龈卟啉单胞菌诱导结肠癌细胞PD-L1上调

程序性死亡配体 1 (PD-L1) 是程序性死亡受体 (PD-1) 的配体，在细胞介导的免疫反应中起主要作用；它调节 T 细胞活化并调节活化 T 细胞的存活和功能。PD-L1的表达可以诱导慢性炎症并激活免疫逃避机制。PD-L1 在大多数人类癌症中表达。牙龈卟啉单胞菌（P. gingivalis）是牙周炎的主要关键病原体，它侵入宿主细胞并处理多种毒力因子。本研究的目的是阐明在结肠癌细胞中诱导 PD-L1 上调的牙龈卟啉单胞菌分子的信号通路。此外，还研究了牙龈卟啉单胞菌的哪些成分负责 PD-L1 诱导。用总膜 (TM) 组分、肽聚糖 (PDG) 和活的牙龈卟啉单胞菌刺激结肠癌细胞 (CL-11)细菌。使用了七种信号分子抑制剂：受体相互作用的丝氨酸/苏氨酸蛋白激酶 2 (RIP2) 酪氨酸激酶抑制剂、核苷酸结合寡聚结构域 (NOD) 样受体 1 和 2 抑制剂、NOD 样受体、核因子 kappa B 抑制剂、c -Jun N-末端激酶抑制剂、丝裂原活化蛋白/细胞外信号调节激酶抑制剂、丝裂原活化激酶 (MAPK) 抑制剂。通过蛋白质印迹分析和定量实时PCR检查PD-L1蛋白表达。证明了TM部分和PDG诱导结肠癌细胞中PD-L1表达的上调。总之，本研究的结果表明，牙龈卟啉单胞菌的 PDG在结肠癌细胞中 PD-L1 上调中起主要作用。此外，PD-L1 上调的机制依赖于 NOD 1 和 NOD 2，并涉及 RIP2 和 MAPK 信号通路的激活。