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Inhibition of BET bromodomains alleviates inflammation in human RPE cells
M Hytti1, P Tokarz2, E Määttä3
1School 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.
Biochemical Pharmacology
|April 24, 2016
Summary
Bromodomain inhibitors reduced inflammation and cell death in retinal cells. These compounds show potential for treating inflammatory eye diseases like age-related macular degeneration.
Area of Science:
- Ophthalmology
- Molecular Biology
- Pharmacology
Background:
- Bromodomain proteins regulate pro-inflammatory gene expression.
- Dysregulated inflammation is implicated in diseases like age-related macular degeneration (AMD).
- Targeting bromodomain interactions offers a potential therapeutic strategy for inflammatory conditions.
Purpose of the Study:
- To evaluate the anti-inflammatory and cytoprotective effects of known bromodomain inhibitors (JQ-1, PFI-1, IBET-151).
- To assess these effects in human retinal pigment epithelial cells (ARPE-19) exposed to etoposide.
- To investigate the roles of NF-κB and SIRT1 in the observed inflammatory signaling.
Main Methods:
- Human retinal pigment epithelial cells (ARPE-19) were treated with etoposide and bromodomain inhibitors.
- Enzyme-linked immunosorbent assay (ELISA) was used to measure cytokine release (IL-6, IL-8) and assess anti-inflammatory effects.
- Western blotting and siRNA-mediated knockdown were employed to investigate the involvement of NF-κB and SIRT1.
Main Results:
- Bromodomain inhibitors significantly reduced etoposide-induced release of IL-6 and IL-8 in ARPE-19 cells.
- The anti-inflammatory effects were independent of SIRT1 activity.
- Bromodomain inhibitors decreased p53 acetylation at the SIRT1 deacetylation site, suggesting downstream effects.
Conclusions:
- Bromodomain inhibitors possess anti-inflammatory properties in human retinal pigment epithelial cells.
- These findings suggest bromodomain inhibitors as a potential therapeutic avenue for managing inflammation in age-related macular degeneration.
- Further research is warranted to explore the therapeutic potential of bromodomain inhibitors in AMD treatment.
