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Regulation of MMPs and TIMPs by IL-1ß during Corneal Ulceration and Infection

¹From the Cooperative Research Centre for Eye Research and Technology and Cornea and Contact Lens Research Unit, School of Optometry and Vision Science, and ²Inflammation Research Unit, School of Medical Sciences, Department of Pathology, The University of New South Wales, Sydney, New South Wales, Australia.

PURPOSE. This study was conducted to investigate the role of IL-1ß in the regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in a mouse model of experimental keratitis and corneal injury.

METHODS. Mice were injected subconjunctivally with 10 µg of anti-mouse IL-1ß antibody 2 hours before challenge with Pseudomonas aeruginosa (strain 6294). Control animals received an equal volume and concentration of isotype control antibody at the same time. Eyes were enucleated at 0, 8, 24, and 72 hours, after bacterial challenge and processed for histologic examination. Some eyes were homogenized and used to evaluate production of MMP-2, MMP-9, TIMP-1, and TIMP-2 protein, by zymography and reverse zymography.

RESULTS. Injury without bacterial infection resulted in increases in both MMP-2 and -9 and a slight but significant downregulation of TIMP-1. Administration of anti-IL-1ß just before injury and without bacterial infection resulted in a significant reduction in expression of MMP-2 (at 8 hours), MMP-9 (at 8 hours), TIMP-1 (at 8 and 72 hours), and TIMP-2 (at 8 hours). Mice treated with anti-IL-1ß antibody, before bacterial challenge, demonstrated markedly reduced corneal damage compared with the severe corneal injury and massive neutrophil infiltration observed in infected mice treated with control antibody. Administration of the neutralizing anti-IL-1ß antibody resulted in a significant reduction of MMP-9 and a change in the time course of TIMP-1 and -2 expression. The reduction in MMP-9 by anti-IL-1ß during infection was much greater than the reduction without infection.

CONCLUSIONS. The results imply that IL-1ß has a central role in corneal destruction during bacterial keratitis and suggests that targeting IL-1ß may be a novel therapeutic strategy for microbial keratitis.

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