Journal of Leukocyte Biology
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Originally published online as doi:10.1189/jlb.0506342 on January 18, 2007

Published online before print January 18, 2007
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(Journal of Leukocyte Biology. 2007;81:1012-1021.)
© 2007 by Society for Leukocyte Biology

Interleukin-18 regulates pathological intraocular neovascularization

Hong Qiao*, Koh-Hei Sonoda*,1, Yasuhiro Ikeda*, Takeru Yoshimura*, Kuniaki Hijioka*, Young-Joon Jo*, Yukio Sassa*, Chikako Tsutsumi-Miyahara*, Yasuaki Hata*, Shizuo Akira{dagger} and Tatsuro Ishibashi*

* Department of Ophthalmology, Graduate School of Medicine, Kyushu University, Fukuoka, Japan; and
{dagger} Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

1 Correspondence: Kyushu University, Ophthalmology, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan. E-mail: sonodak{at}med.kyushu-u.ac.jp

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.

Key Words: rodent • cytokine • inflammation






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