Interleukin-18 regulates pathological intraocular neovascularization

Abstract

Recently, the proinflammatory cytokine IL-18 has been shown to have a role in angiogenesis. This study aimed to elucidate its role in abnormal neovascularization (NV) in an oxygen-induced retinopathy (OIR) mouse model of the retinopathy seen in human premature newborns. IL-18 was constitutively expressed in the retina in C57BL/6 mice, but expression transiently dropped on Day 17 after birth in mice exposed to 75% oxygen for 5 days between Days 7 and 12. Coincident with the IL-18 reduction in oxygen-treated mice, vascular endothelial growth factor was expressed in the retina, and OIR developed. By Day 24, NV in the retina had regressed to normal levels. By contrast, IL-18 knockout mice, exposed to elevated oxygen concentrations, developed more severe OIR on Day 17, and it is important that this persisted until Day 24. This suggested that IL-18 negatively regulated retinal NV. To investigate this further, we administrated recombinant IL-18 to C57BL/6 mice during the development of OIR but found no significant inhibition of retinopathy. However, when IL-18-binding protein was administered during the OIR recovery phase to neutralize endogenous IL-18, OIR was still apparent on Day 24. We therefore concluded that IL-18 regulates pathogenic retinal NV by promoting its regression rather than inhibiting its development. This suggests some useful, new approaches to treating retinopathy in humans.

Immunotherapeutic Approach for Better Management of Cancer - Role of IL-18

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Interleukin 18 induces angiogenesis in vitro and in vivo via Src and Jnk kinases

“…We and others have shown that IL-18 promotes endothelial cell migration and is a direct angiogenic mediator in vitro and in vivo 4 24 25. IL-18 induces hypoxia inducible factor-1α (HIF-1α) through the activity of the GTPase Rac1, and increases HIF-1α-mediated tumour progression and metastasis 26.…”

Protective Effect of Intravitreal Administration of Tresperimus, an Immunosuppressive Drug, on Experimental Autoimmune Uveoretinitis

“…37 Interestingly, IL-18 regulates pathogenic retinal neovascularization by promoting regression of abnormal neovascularization in an oxygen-induced retinopathy mouse model. 38 Intraretinal and subretinal neovascularization were observed during EAU, 39 with an imbalance between VEGF and TGF-␤. 40 The role of IL-18 in EAU is not clearly identified.…”