Inhibition of BET bromodomains alleviates inflammation in human RPE cells.
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.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland; Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
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Hytti
Department of Molecular Genetics, University of Lodz, ul. Pomorska 141/143, 90-236 Lodz, Poland.
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Tokarz
Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
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Määttä
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland; Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
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Piippo
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland; Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
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Korhonen
Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
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Suuronen
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
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Honkakoski
Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, Puijonlaaksontie 2, 70210 Kuopio, Finland.
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Kaarniranta
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
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Lahtela-Kakkonen
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland. Electronic address: anu.kauppinen@uef.fi.
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Kauppinen
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005047:Etoposide / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains; D011725:Pyridines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
D000893:Anti-Inflammatory Agents; D053961:Azabicyclo Compounds; D001381:Azepines; D001569:Benzodiazepines; D002227:Carbazoles; D005047:Etoposide; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D011725:Pyridines; D034741:RNA, Small Interfering; D056564:Sirtuin 1; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D000093242:Interleukin-6 Inhibitors; C561695:(+)-JQ1 compound; C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; C508600:IL6 protein, human; C000603674:PF-06687252; C554645:molibresib; C447939:SIRT1 protein, human
Age-related macular degeneration; Bromodomains; Etoposide (PubChem CID: 36462); IBET-151 (PubChem CID: 52912189); Inflammation; JQ-1 (PubChem CID: 46907787); PFI-1 (PubChem CID: 71271629); Retinal pigment epithelium; Sirtuin 1