Mono ADP-ribosylation inhibitors prevent inflammatory cytokine release in alveolar epithelial cells
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A549, a type II alveolar epithelial cell line stimulated with LPS (10 μg/ml), released high levels of the inflammatory cytokines IL-6 and IL-8. Here, we have investigated whether ADP-ribosylation inhibitors block the LPS-triggered cytokine release in epithelial cells. When coincubating A549 with LPS and meta-iodobenzylguanidine or novobiocin, selective arginine-dependent ART-inhibitors, the release of IL-6 and IL-8 was inhibited in a concentration-dependent manner. This effect has been linked with the presence of a functionally active arginine ADP-ribosylating enzyme on the cell surface. To this aim, we amplified by RT-PCR the ART1 transcript and identified four ADP-ribosylated proteins likely substrate for ART1. The mechanism behind the cytokine inhibition in epithelial cells seems to be correlated with the presence of ART1, which behaves as an essential positive regulator of inflammatory cytokines. This novel observation indicates this enzyme as well as other novobiocin/MIBG sensitive ARTs as potential targets for the development of new therapeutic strategies.
KeywordsLPS TLR-4 ADP-ribosylation inhibitors Epithelial cells Cytokines
Toll like receptor 4
The authors wish to thank Simona Tavarini for her excellent technical support in cytokine quantification, Giorgio Corsi for artwork, Elisabetta Soldaini for critical reading of the manuscript and Valerio Reguzzi for his assistance with statistical analysis. This work was supported by Novartis Vaccines and by Murst (fondo Ateneo ex 60%).
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