pf-06687252 and Inflammation

Bromodomain-containing proteins are vital for controlling the expression of many pro-inflammatory genes. Consequently, compounds capable of inhibiting specific bromodomain-facilitated protein-protein interactions would be predicted to alleviate inflammation, making them valuable agents in the treatment of diseases caused by dysregulated inflammation, such as age-related macular degeneration. Here, we assessed the ability of known inhibitors JQ-1, PFI-1, and IBET-151 to protect from the inflammation and cell death caused by etoposide exposure in the human retinal pigment epithelial cell line, ARPE-19. The potential anti-inflammatory effects of the bromodomain inhibitors were assessed by ELISA (enzyme-linked immunosorbent assay) profiling. The involvement of NF-κB and SIRT1 in inflammatory signaling was monitored by ELISA and western blotting. Furthermore, SIRT1 was knocked down using a specific siRNA or inhibited by EX-527 to elucidate its role in the inflammatory reaction. The bromodomain inhibitors effectively decreased etoposide-induced release of IL-6 and IL-8. This anti-inflammatory effect was not related to SIRT1 activity, although all bromodomain inhibitors decreased the extent of acetylation of p53 at the SIRT1 deacetylation site. Overall, since bromodomain inhibitors display anti-inflammatory properties in human retinal pigment epithelial cells, these compounds may represent a new way of alleviating the inflammation underlying the onset of age-related macular degeneration.

Topics: Anti-Inflammatory Agents; Azabicyclo Compounds; Azepines; Benzodiazepines; Carbazoles; Cell Line; Cell Survival; Epithelial Cells; Etoposide; Gene Expression Regulation; Humans; Inflammation; Interleukin-6; Interleukin-8; Models, Biological; NF-kappa B; Protein Domains; Pyridines; Retinal Pigment Epithelium; RNA, Small Interfering; Signal Transduction; Sirtuin 1; Topoisomerase II Inhibitors; Transcription Factors; Triazoles; Tumor Suppressor Protein p53