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J. Biol. Chem. 280 (35): 31240-31248

© 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

Involvement of Inflammation, Degradation, and Apoptosis in a Mouse Model of Glaucoma*{diamondsuit}

Xiaohong Zhou{ddagger}§¶, Feng Li{ddagger}§, Li Kong{ddagger}§, Hiroshi Tomita||, Chao Li{ddagger}§, , and Wei Cao{ddagger}§**

Department of {ddagger}Ophthalmology, §Dean A. McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, the ||Biofunctional Science Biomedical Engineering Research Organization, Tohoku University, Sendai, Miyagi 980-8575, Japan, and the West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China

Abstract: Glaucoma is a common cause of blindness affecting at least 66 million people worldwide. Pigmentary glaucoma is one of the most common forms of secondary glaucoma, and its pathogenesis remains unclear. Interleukin-18 (IL-18) is an important regulator of innate and acquired immune responses and plays an important role in inflammatory/autoimmunity diseases. Using the DBA/2J mouse as an animal model of human pigmentary glaucoma, we demonstrated for the first time that the expression of the IL-18 protein and gene in the iris/ciliary body and level of IL-18 protein in the aqueous humor of DBA/2J mice are dramatically increased with age. This increase precedes the onset of clinical evidence of pigmentary glaucoma, implying a pathogenic role of inflammation/immunity in this disease. We also observed that activated NF-{kappa}B and phosphorylated MAPK are increased in the iris/ciliary body of DBA/2J mice, suggesting that both signaling pathways may be involved in IL-18 mediated pathogenesis of pigmentary glaucoma in the eyes of DBA/2J mice. In addition, matrix metalloproteinase-2 (MMP-2) expression in the iris/ciliary body and the activity of MMP-2 in the aqueous humor are increased whereas tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) expression in the iris/ciliary body is decreased, indicating that the degradation process is involved in this mouse model of pigmentary glaucoma. Furthermore, the expressions of apoptosis-related genes, caspase-8, Fas, FADD, FAP, and FAF, and the activity of caspase-3 are increased in the iris/ciliary body of DBA/2J mice. Elucidation of biochemical and molecular mechanisms of IL-18 participation in the pathogenesis of pigmentary glaucoma should provide approaches for developing improved and targeted treatments to ameliorate this blinding disease. The possibility that altered IL-18 expression in the eye of DBA/2J mice initiates and/or amplifies the pathogenesis of pigmentary glaucoma requires further investigation.

Received for publication March 10, 2005. Revision received June 13, 2005.

* This work was supported by National Institutes of Health (NIH) Grant P20 RR17703 from the Centers of Biomedical Research Excellence program of the National Center for Research Sources, NIH/NEI Grants EY014427 and EY12190, and an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{diamondsuit} This article was selected as a Paper of the Week.

** To whom correspondence should be addressed: Dept. of Ophthalmology, University of Oklahoma Health Sciences Center, Dean A. McGee Eye Inst., 608 Stanton L. Young Blvd., Oklahoma City, OK 73104. Tel.: 405-271-3370; Fax: 405-271-3721; E-mail: wei-cao{at}

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