IL-6 Exacerbates Oxidative Damage of RPE Cells by Indirectly Destabilizing the mRNA of DNA Repair Genes.

Abstract

Chronic inflammation has been associated with the progression of age-related macular degeneration (AMD) and diabetic retinopathy (DR), and the levels of various inflammatory factors are significantly increased in intraocular fluids of patients with AMD and DR. Therefore, elucidating the roles of inflammatory factors in the oxidative damage of RPE cells will help uncover the pathogenesis of AMD and DR. We have previously demonstrated that E2F1 plays an important role in the antioxidant capacity of RPE cells. Here, our transcriptome analysis shows that E2F1 affected the expressions of DNA repair genes in RPE cells. In addition, we found that E2F1 transactivated the splicing factor SRSF1. SRSF1 knockdown promoted DNA oxidative damage and apoptosis and decreased the mRNA stability of DNA repair genes XRCC2, POLK and LIG4 in RPE cells. Moreover, we found that SRSF1 could bind to the RNA stabilizing factor MATR3, and knockdown of the latter affected the mRNA stability of these DNA repair genes. Notably, interleukin-6 (IL-6), an inflammatory factor upregulated in intraocular fluids of patients with AMD and DR, decreased SRSF1 expression by inducing acetylation of E2F1 at the K125 position. Consistently, SRSF1 overexpression relieved IL-6-induced DNA oxidative damage and apoptosis in RPE cells. In vivo experiment results also confirmed that IL-6 could aggravate retinal oxidative damage. In conclusion, high levels of IL-6 in the eyes of patients with AMD and DR destabilize the mRNAs of DNA repair genes by disrupting the expression of SRSF1, leading to abnormal repair of DNA oxidative damage in RPE cells.