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Sarah Doyle, Peter S Adamson, Francisco J Lopez, Peter Humphries, Matthew Campbell; IL-18 promotes wound healing and has anti-angiogenic properties in the eye. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2462.
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Age-related macular degeneration (AMD) is the leading cause of central vision loss in the developed world. Although choroidal neovascularization (CNV) is the less common end stage of disease, it accounts for ~90% of blindness caused by the disease. We live in an aging society witnessing a steady rise in obesity. This obesity epidemic is contributing to increasing incidence of diabetes. Diabetic retinopathy (DR) is the primary cause of vision loss in people of working age with 99% of Insulin-dependent diabetics affected within 20 years. Current anti-VEGF (Vascular endothelial growth factor) therapies have revolutionized treatment for ‘neovascular’ AMD and DR and directly implicate VEGF as a key regulator of pathological vasopermeability and angiogenesis. However, the importance of VEGF’s role as a neuronal survival factor cannot be overlooked, underscored by the observation that in patients receiving long-term anti-VEGF therapy the neural retina can begin to degenerate resulting in further vision loss. For this reason tailoring therapies to attenuate specific signal transduction cascades, reducing the side effects of “anti-VEGF” treatment holds significant therapeutic promise.<br /> We discovered that IL-18 controls CNV formation in mice with no effect on retinal pigment epithelial (RPE) cell viability at therapeutic doses. The potential use of recombinant IL-18 as an immunotherapy is proving itself safe and efficacious at every step, however, its use as a direct immunotherapy remains controversial. Therefore, it is imperative that we map out the signaling cascades initiated in response to IL-18 that result in the anti-angiogenic and anti-permeability phenotype.
Primary human retinal microvascular endothelial cells and RPE cells were treated with various doses of IL-18, VEGF or both, over time and assayed by qPCR, Western Blot and ELISA.
Compellingly, our studies have indicated that IL-18 specifically inhibits the VEGF/VEGFR2 signaling axis. VEGFR2 signaling appears to be mainly involved in promoting vascular permeability and angiogenesis, whereas VEGFR1 promotes cell survival, therefore designing therapies that block VEGFR2 signaling specifically would have the most impact.
Our data indicates that the signal transduction pathways elicited by IL-18 hold within them the key to the rational design of a new generation of tailored anti-angiogenesis therapies.
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