Published online before print August 9, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070172

Accepted for publication May 24, 2007.

Article

Dexamethasone Inhibits Interleukin-1-Induced Corneal Neovascularization. Role of Nuclear Factor-B-Activated Stromal Cells in Inflammatory Angiogenesis

Shintaro Nakao^*, Yasuaki Hata^*@, Muneki Miura^*, Kousuke Noda, Yusuke N. Kimura, Shuhei Kawahara^*, Takeshi Kita^*, Toshio Hisatomi^*, Toru Nakazawa, Yiping Jin^¶, M. Reza Dana^¶, Michihiko Kuwano, Mayumi Ono^||, Tatsuro Ishibashi^*, and Ali Hafezi-Moghadam

From the Departments of Ophthalmology,* and Medical Biochemistry,^|| Graduate School of Medical Sciences, and Collabo-Station II, Kyushu University, Fukuoka, Japan; the Research Center of Innovative Cancer Therapy of the 21st Century Center of Excellence (COE) Program for Medical Science, Kurume University, Fukuoka, Japan; and the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, and Schepens Eye Research Institute,^¶ Harvard Medical School, Boston, Massachusetts

^@ To whom correspondence should be addressed. E-mail: hatachan{at}med.kyushu-u.ac.jp.

	Abstract

Dexamethasone, a synthetic corticosteroid, is widely used as a potent anti-inflammatory drug in various diseases including corneal angiogenesis. However, dexamethasone's impact on interleukin (IL)-1-dependent inflammatory angiogenesis is unknown. Here, we show that dexamethasone inhibits IL-1-induced neovascularization and the expression of the angiogenesis-related factors, vascular endothelial growth factor-A, KC, and prostaglandin E₂ in the mouse cornea 2 days after IL-1 implantation. IL-1 caused IB- phosphorylation in corneal stromal cells but not in infiltrated CD11b⁺ cells 2 days after IL-1 implantation. In contrast, both cell types were positive for phosphorylated IB- 4 days after IL-1 implantation. Dexamethasone significantly inhibited IB- phosphorylation 2 and 4 days after IL-1 implantation. Furthermore, dexamethasone inhibited IL-1-induced expression of vascular endothelial growth factor-A, KC, and prostaglandin E₂, and signaling of nuclear factor (NF)-B in corneal fibroblasts in vitro. A selective NF-B inhibitor attenuated IL-1-induced corneal angiogenesis. These findings suggest that NF-B activation in the corneal stromal cells is an important early event during IL-1-induced corneal angiogenesis and that dexamethasone inhibits IL-1-induced angiogenesis partially via blocking NF-B signaling.

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