Journal
BIOCHEMICAL PHARMACOLOGY
Volume 110, Issue -, Pages 71-79Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2016.04.009
Keywords
Inflammation; Bromodomains; Sirtuin 1; Retinal pigment epithelium; Age-related macular degeneration
Categories
Funding
- Finnish Cultural Foundation - North-Savo
- Central Foundations
- Academy of Finland
- Kuopio University Hospital
- Alfred Kordelin Foundation
- Paivikki ja Sakari Sohlbergin Saatio
- Emil Aaltonen Foundation
- Sokeain Ystavat ry
- Silma-ja Kudospankkisaatio
- Silmasaatio
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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-kappa B 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. (C) 2016 Elsevier Inc. All rights reserved.
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