Oxidative stress modulates complement factor H expression in retinal pigmented epithelial cells by acetylation of FOXO3.
Age-related macular degeneration (AMD), the leading cause of severe vision loss in the elderly, is a complex disease that results from genetic modifications that increase susceptibility to environmental exposures. Smoking, a major source of oxidative stress, increases the incidence and severity of AMD, and antioxidants slow progression, suggesting that oxidative stress plays a major role. Polymorphisms in the complement factor H (CFH) gene that reduce activity of CFH increase the risk of AMD. In this study we demonstrate an interaction between these two risk factors, because oxidative stress reduces the ability of an inflammatory cytokine, interferon-gamma, to increase CFH expression in retinal pigmented epithelial cells. The interferon-gamma-induced increase in CFH is mediated by transcriptional activation by STAT1, and its suppression by oxidative stress is mediated by acetylation of FOXO3, which enhances FOXO3 binding to the CFH promoter, reduces its binding to STAT1, inhibits STAT1 interaction with the CFH promoter, and reduces expression of CFH. Expression of SIRT1, a mammalian homolog of NAD-dependent protein deacetylase sir2, attenuated FOXO3 recruitment to the CFH regulatory region and reversed the H(2)O(2)-induced repression of CFH gene expression. These data suggest an important interaction between environmental exposure and genetic susceptibility in the pathogenesis of AMD and, by elucidating molecular signaling involved in the interaction, provide potential targets for therapeutic intervention.
Wu
Zhihao
Z
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
Lauer
Thomas W
TW
Sick
Anna
A
Hackett
Sean F
SF
Campochiaro
Peter A
PA
D000107:Acetylation; D017242:Complement Factor H / Q000096:biosynthesis* / Q000737:chemistry*; D016207:Cytokines / Q000378:metabolism; D004777:Environment; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D018384:Oxidative Stress; D010857:Pigment Epithelium of Eye / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011485:Protein Binding; D015398:Signal Transduction
D016207:Cytokines; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D017242:Complement Factor H; D007371:Interferon-gamma