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James M. Hill, Christian Clement, Pranab K. Mukherjee, Jian-Guo Cui, Yuan Yuan Li, Surjyadipta Bhattacharjee, Harris E. McFerrin, Jr., Partha S. Bhattacharjee, Yuhai Zhao, Walter J. Lukiw; Acyclovir Attenuates Stress-Induced miRNA-146a Levels in Human Retinal Pigment Epithelial (RPE) Cells. Invest. Ophthalmol. Vis. Sci. 2012;53(14):789.
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Retinal pigment epithelial (RPE) cells rely on a defined population of micro RNAs (miRNAs) to shape their homeostatic patterns of gene expression. In these studies we analyzed the effects of physiologically relevant cytokine stressors (TNF alpha and IL-1 beta) on miRNA speciation in human RPE cells to study what specific gene expression pathways were altered. As acyclovir has been previously reported to quench elective pro-inflammatory miRNA signaling (Lukiw et al., Neuroreport 21:922-927, 2010), we also tested the effects of this potent acyclic nucleoside anti-viral drug under the same experimental conditions.
ARPE-19 cell culture; IL-1 beta- and/or TNF alpha-induced stress; bioinformatics; DNA array; human retinal tissue; human retinal and brain cells in primary culture; gel shift assay; micro-RNA array; Northern micro-dot blot analysis; RT-PCR; transfection assay; Western immunohistochemistry
In IL-1 beta- and/or TNF alpha-stressed human RPE cells we identified several retinal-abundant miRNA species that are consistently up-regulated including the pro-inflammatory miRNA-146a species. Up-regulation of this inducible, NF-kB-regulated, 22 nucleotide small non-coding RNA (sncRNA) is associated with altered innate-immune responses in stressed human brain cells in Alzheimer’s and prion-linked neurodegenerative disease and in age-related macular degeneration (AMD) [p<0.01, ANOVA]. Acyclovir was found to quench this effect restoring miRNA-146a back to homeostatic levels.
Dysfunctional inflammatory signaling in RPE cells appears to be involved in a number of progressive human retinal disorders including AMD. These data provide the first evidence of altered miRNA signaling in cytokine-stressed human RPE cells. Dissection of the interactive molecular contributions of NF-ΚB-, and miRNA-146a-mediated signaling mechanisms in stressed RPE cells should provide further therapeutic insight into potential inhibitors that will be useful in retinal cell pharmacotherapy and RPE-associated disease.
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