Abstract
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.
Highlights
The airway epithelium plays a critical role in the first line of defense against respiratory pathogens
In this study we tested if new aroylated phenylenediamines (APDs), designated HO53 and HO56 could stimulate innate immunity responses in airway epithelial cells by enhancing the expression of endogenous antimicrobial peptide (AMP) and if that response was effective against the respiratory pathogen Pseudomonas aeruginosa PAO1 strain
Using the previously described luciferase reporter HT29 colonic cell line for expression-analysis of the antimicrobial peptide LL-3735, we identified, among the novel APDs, HO53 and HO56 (Fig. 1a; Supplementary Figs S1 and S2; Supplementary Methods) as interesting AMP-inducers with high activity but reduced toxicity
Summary
The airway epithelium plays a critical role in the first line of defense against respiratory pathogens. The induction of endogenous AMPs could be an effective way of treating infections because many MDR strains are susceptible to different AMPs. Several different compounds inducing expression of AMPs to boost innate immunity have been shown effective in animal models and clinical trials for treatment of infectious diseases, e.g. pulmonary tuberculosis[21,22]. It has been shown that Entinostat stimulates CAMP gene expression via activation of STAT3 and HIF-1α transcription factors in human colonic epithelial cells[29]. In this study we tested if new APDs, designated HO53 and HO56 could stimulate innate immunity responses in airway epithelial cells by enhancing the expression of endogenous AMPs and if that response was effective against the respiratory pathogen Pseudomonas aeruginosa PAO1 strain. In human bronchial epithelial cell lines, the new APDs markedly induced expression of the CAMP gene (encoding cathelicidin pro-LL-37/LL-37) both in monolayer and in ALI. The current study might open up possibilities for using APDs as novel innate immunity modulators for host directed therapy (HDT) of infectious diseases
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