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Simultaneous study of matrix metalloproteinases, proinflammatory cytokines, and soluble cytokine receptors in the tears of noninfectious corneal ulcer patients



We investigated the presence of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), proinflammatory cytokines, and soluble cytokine receptors in the tear fluid of patients with noninfectious corneal ulcers in the peripheral cornea.


The subjects were 20 eyes of 17 patients with peripheral noninfectious corneal ulcers and 20 eyes of 20 volunteers. Tear samples were taken by the Schirmer test I method and the presence of MMPs (MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, and MMP-13) and TIMPs (TIMP-1, TIMP-2, and TIMP-4) were investigated using an MMP antibody array system. The concentrations of proinflammatory cytokines {IL-1β, IL-6, and TNF-α (tumor necrosis factor-alpha)} and soluble cytokine receptors {soluble (s) IL-1R1, sIL-1R2, sIL-2Rα, sIL-4R, sIL-6R, sTNFR1, sTNFR2, s-vascular endothelial growth factor receptor (VEGFR) 1, sVEGFR2, sVEGFR3, and sgp130} were determined using the multiplex bead immunoassay system.


The concentrations of MMP-8 and MMP-9 were significantly up-regulated in the tear fluid of the ulcer patients, whereas TIMPs concentrations did not change. The concentrations of IL-1β, IL-6, sIL-1R2, sIL-6R, sTNFR1, and sTNFR2 were up-regulated in the ulcer patients, whereas sgp130 and sVEGFR1 concentrations significantly decreased.


The presence of some MMPs increased significantly in the patients with peripheral noninfectious corneal ulcers, whereas the presence of TIMPs remained unchanged. Although some proinflammatory cytokines were up-regulated, their antagonists, soluble cytokine receptors, were also up-regulated. It is thus possible that the up-regulation of MMPs disrupts the balance between the MMPs and TIMPs and that this balance may play a pivotal role in the pathophysiology of corneal ulceration.

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The study reported in this paper was supported by the Ministry of Education, Culture, Sports, Science and Technology, Grant-in-Aid for Young Scientists (B) 23792010 (to TS, FY2011-FY2012).

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Correspondence to Tohru Sakimoto.

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Sakimoto, T., Ohnishi, T. & Ishimori, A. Simultaneous study of matrix metalloproteinases, proinflammatory cytokines, and soluble cytokine receptors in the tears of noninfectious corneal ulcer patients. Graefes Arch Clin Exp Ophthalmol 252, 1451–1456 (2014).

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  • Matrix metalloproteinase
  • Noninfectious corneal ulcer
  • Soluble cytokine receptor
  • Tissue inhibitors of metalloproteinase