Biomedical Center, University of Iceland, Reykjavik, 101, Iceland.
Department of Biosciences and Nutrition, Karolinska Institutet, S-14183, Huddinge, Sweden.
Sci Rep. 2019 May 8;9(1):7114. doi: 10.1038/s41598-019-43350-z.
Aroylated phenylenediamines (APDs) are novel inducers of innate immunity enhancing cathelicidin gene expression in human bronchial epithelial cell lines. Here we present two newly developed APDs and aimed at defining the response and signaling pathways for these compounds with reference to innate immunity and antimicrobial peptide (AMP) expression. Induction was initially defined with respect to dose and time and compared with the APD Entinostat (MS-275). The induction applies to several innate immunity effectors, indicating that APDs trigger a broad spectrum of antimicrobial responses. The bactericidal effect was shown in an infection model against Pseudomonas aeruginosa by estimating bacteria entering cells. Treatment with a selected APD counteracted Pseudomonas mediated disruption of epithelial integrity. This double action by inducing AMPs and enhancing epithelial integrity for one APD compound is unique and taken as a positive indication for host directed therapy (HDT). The APD effects are mediated through Signal transducer and activator of transcription 3 (STAT3) activation. Utilization of induced innate immunity to fight infections can reduce antibiotic usage, might be effective against multidrug resistant bacteria and is in line with improved stewardship in healthcare.
芳酰化苯二胺（APD）是新型的天然免疫增强剂，可诱导人支气管上皮细胞系中防御素基因的表达。本研究中我们介绍了两种新开发的 APD，并旨在确定这些化合物的反应和信号通路，以参考天然免疫和抗菌肽（AMP）的表达。首先根据剂量和时间来确定诱导作用，并与 APD 依曲替酯（MS-275）进行比较。诱导作用适用于几种天然免疫效应物，表明 APD 可引发广谱的抗菌反应。通过估计进入细胞的细菌，在针对铜绿假单胞菌的感染模型中显示了杀菌作用。用选定的 APD 处理可抵抗铜绿假单胞菌介导的上皮完整性破坏。这种诱导 AMP 产生和增强上皮完整性的双重作用对于一种 APD 化合物来说是独特的，并被视为宿主导向治疗（HDT）的积极指征。APD 的作用是通过信号转导和转录激活因子 3（STAT3）的激活来介导的。利用诱导的天然免疫来抵抗感染可以减少抗生素的使用，可能对多药耐药菌有效，并且符合医疗保健中改进的管理。
