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Involvement of Inflammation, Degradation, and Apoptosis in a Mouse Model of Glaucoma*
Xiaohong Zhou¶,
Feng Li,
Li Kong,
Hiroshi Tomita||,
Chao Li, , and
Wei Cao**
Department of 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 66million people worldwide. Pigmentary glaucoma is one of themost common forms of secondary glaucoma, and its pathogenesisremains unclear. Interleukin-18 (IL-18) is an important regulatorof innate and acquired immune responses and plays an importantrole in inflammatory/autoimmunity diseases. Using the DBA/2Jmouse as an animal model of human pigmentary glaucoma, we demonstratedfor the first time that the expression of the IL-18 proteinand gene in the iris/ciliary body and level of IL-18 proteinin the aqueous humor of DBA/2J mice are dramatically increasedwith age. This increase precedes the onset of clinical evidenceof pigmentary glaucoma, implying a pathogenic role of inflammation/immunityin this disease. We also observed that activated NF-B and phosphorylatedMAPK are increased in the iris/ciliary body of DBA/2J mice,suggesting that both signaling pathways may be involved in IL-18mediated pathogenesis of pigmentary glaucoma in the eyes ofDBA/2J mice. In addition, matrix metalloproteinase-2 (MMP-2)expression in the iris/ciliary body and the activity of MMP-2in the aqueous humor are increased whereas tissue inhibitorof matrix metalloproteinase-1 (TIMP-1) expression in the iris/ciliarybody is decreased, indicating that the degradation process isinvolved 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 increasedin the iris/ciliary body of DBA/2J mice. Elucidation of biochemicaland molecular mechanisms of IL-18 participation in the pathogenesisof pigmentary glaucoma should provide approaches for developingimproved and targeted treatments to ameliorate this blindingdisease. The possibility that altered IL-18 expression in theeye of DBA/2J mice initiates and/or amplifies the pathogenesisof 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 Excellenceprogram of the National Center for Research Sources, NIH/NEIGrants EY014427 and EY12190, and an unrestricted grant fromResearch to Prevent Blindness to the Department of Ophthalmology.The costs of publication of this article were defrayed in partby the payment of page charges. This article must thereforebe hereby marked "advertisement" in accordance with 18 U.S.C.Section 1734 solely to indicate this fact.
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}ouhsc.edu.
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¶,
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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. 
This article was selected as a Paper of the Week. 
