Application of Plasmid DNA Encoding IL-18 Diminishes Development of Herpetic Stromal Keratitis by Antiangiogenic Effects

HSV-1 infection of the eye can cause a blinding immunoinflammatory stromal keratitis (SK) lesion. Using the mouse model, we have demonstrated that angiogenesis is an essential step in lesion pathogenesis because its inhibition results in diminished severity. The molecules involved in causing corneal angiogenesis are multiple and include the vascular endothelial growth factor (VEGF) family of proteins. In this report we show that application of plasmid DNA encoding IL-18 to the cornea of mice before HSV-1 ocular infection resulted in reduced angiogenesis and diminished SK immunoinflammatory lesions. The antiangiogenic effects of IL-18 treatment appeared to be mediated by inhibition of VEGF production in the cornea. We also showed that IL-18 controlled VEGF expression in vitro and also decreased CpG oligodeoxynucleotide induced VEGF-dependent neovascularization. In addition the administration of IL-18-binding protein, an IL-18 antagonist, into the inflammatory eye resulted in elevated angiogenesis and increased VEGF expression. Our results indicate that IL-18 is an important endogenous negative regulator of HSV-induced angiogenesis resulting in reduced SK lesion severity. Our results could mean that IL-18 administration may represent a useful approach to manage unwanted angiogenesis.