Inhibition of BET bromodomains alleviates inflammation in human RPE cells

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• 作者：M. Hytti^a ; ^b ; P. Tokarz^c ; E. Mä ; ä ; ttä ; ^b ; N. Piippo^a ; ^b ; E. Korhonen^a ; ^b ; T. Suuronen^d ; P. Honkakoski^a ; K. Kaarniranta^b ; ^e ; M. Lahtela-Kakkonen^a ; A. Kauppinen^a ; ^{anu.kauppinen@uef.fi" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Etoposide (PubChem CID ; 36462) ; JQ-1 (PubChem CID ; 46907787) ; IBET-151 (PubChem CID ; 52912189) ; PFI-1 (PubChem CID ; 71271629)
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 June 2016
• 年：2016
• 卷：110-111
• 期：Complete
• 页码：71-79
• 全文大小：1076 K

文摘

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.