Regulation of MMPs and TIMPs by IL-1beta during corneal ulceration and infection.
OBJECTIVE
This study was conducted to investigate the role of IL-1beta 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 micro g of anti-mouse IL-1beta 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-1beta 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-1beta 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-1beta 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-1beta during infection was much greater than the reduction without infection.


CONCLUSIONS
The results imply that IL-1beta has a central role in corneal destruction during bacterial keratitis and suggests that targeting IL-1beta may be a novel therapeutic strategy for microbial keratitis.
Xue
Mei Lang
ML
Cooperative Research Centre for Eye Research and Technology and Cornea and Contact Lens Research Unit, School of Optometry and Vision Science, The University of New South Wales, Sydney, New South Wales, Australia.
Wakefield
Denis
D
Willcox
Mark D P
MD
Lloyd
Andrew R
AR
Di Girolamo
Nick
N
Cole
Nerida
N
Thakur
Archana
A
D000818:Animals; D003315:Cornea / Q000201:enzymology / Q000382:microbiology; D003320:Corneal Ulcer / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D004591:Electrophoresis, Polyacrylamide Gel; D015818:Eye Infections, Bacterial / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D007375:Interleukin-1 / Q000276:immunology / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000276:immunology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011552:Pseudomonas Infections / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000502:physiology; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D015854:Up-Regulation
D007375:Interleukin-1; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9