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Lynn Hassman, Steven Pollock, Richard P Phipps; Specialized pro-resolving mediators (SPMs) promote resolution of inflammation in human retinal pigment epithelial cells.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1860.
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© ARVO (1962-2015); The Authors (2016-present)
Intraocular inflammation can have devastating visual effects when it involves the retina. Inflammation resolution is an active process mediated by a family of endogenous lipid molecules, termed specialized pro-resolving mediators (SPMs), which derive from dietary omega fatty acids. We investigated the ability of SPMs to mitigate inflammation in retinal pigment epithelial (RPE) cells, which are strategically located at the blood-retina barrier as gatekeepers of intraocular inflammation.
We induced inflammation in 0.1% serum-starved ARPE-19 monolayers with IL-1β (40-5000ng/ml) or vehicle (BSA). We analyzed the production of pro- and anti-inflammatory cytokine production at 48 hours. We then tested the effects of SPMs, including prototypical Resolvins D1 and D2, the active precursor 17-HDHA, as well as Lipoxins A4 and B4 and Maresin-1 on IL-1β -driven cytokine production by pre-incubating ARPE-19 cultures with SPMs (5, 50 and 500nM) or vehicle (ethanol) for 18 hours prior to IL-1β treatment.
IL-1β stimulation strongly increased the production of the pro-inflammatory mediators IL-8, IL-6, MCP-1 and PGE2 and decreased the anti-inflammatory cytokine TGF-β in a dose dependent fashion. While the magnitude of effect varied between individual SPMs, most greatly reduced the production of L-8, IL-6, MCP-1 and PGE2 in ARPE-19 cells. Concurrently, SPMs enhanced production of anti-inflammatory TGFβ. Noteably, Maresin 1 was most effective at reducing pro-inflammatory mediator production, but had minimal effect on TGF β production. Conversely, Lipoxins A4 and B4 had far less inhibitory effect on pro-inflammatory cytokine production, but Lipoxin induced the greatest increase in TGF β production.
These results support the hypothesis that SPMs promote resolution of inflammation in RPE cells by reducing the production of pro-inflammatory IL-8, IL-6, MCP-1 and PGE2 while increasing the production of anti-inflammatory TGFβ. Intriguingly, we found that individual SPMs exert unique and complimentary pro-resolving effects. SPMs represent novel therapeutic targets in inflammatory retinal diseases, such as uveitis and macular degeneration, and for future application to transplant and stem-cell based therapies. Future studies will characterize this phenomenon in primary human RPE cells and investigate the applicability to additional RPE inflammation models.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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