Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Similar content being viewed by others
References
Dana MR, Qian Y, Hamrah P (2000) Twenty-five-year panorama of corneal immunology: emerging concepts in the immunopathogenesis of microbial keratitis, peripheral ulcerative keratitis, and corneal transplant rejection. Cornea 19:625–643
Sivak JM, Fini ME (2002) MMPs in the eye: emerging roles for matrix metalloproteinases in ocular physiology. Prog Retin Eye Res 21:1–14
Gottsch JD, Liu SH, Minkovitz JB, Goodman DF, Srinivasan M, Stark WJ (1995) Autoimmunity to a cornea-associated stromal antigen in patients with Mooren's ulcer. Invest Ophthalmol Vis Sci 36:1541–1547
Messmer EM, Foster CS (1999) Vasculitic peripheral ulcerative keratitis. Surv Ophthalmol 43:379–396
Yagci A (2012) Update on peripheral ulcerative keratitis. Clin Ophthalmol 6:747–754
Jhanji V, Young AL, Mehta JS, Sharma N, Agarwal T, Vajpayee RB (2011) Management of corneal perforation. Surv Ophthalmol 56:522–538
Sakimoto T, Shoji J, Sawa M (2003) Active form of gelatinases in tear fluid in patients with corneal ulcer or ocular burn. Jpn J Ophthalmol 47:423–426
Shoji J, Inada N, Sawa M (2006) Antibody array-generated cytokine profiles of tears of patients with vernal keratoconjunctivitis or giant papillary conjunctivitis. Jpn J Ophthalmol 50:195–204
Clark IM, Swingler TE, Sampieri CL, Edwards DR (2008) The regulation of matrix metalloproteinases and their inhibitors. Int J Biochem Cell Biol 40:1362–1378
Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141:52–67
Toft-Hansen H, Nuttall RK, Edwards DR, Owens T (2004) Key metalloproteinases are expressed by specific cell types in experimental autoimmune encephalomyelitis. J Immunol 173:5209–5218
Matsubara M, Zieske JD, Fini ME (1991) Mechanism of basement membrane dissolution preceding corneal ulceration. Invest Ophthalmol Vis Sci 32:3221–3237
Takahashi H, Igarashi T, Fujimoto C, Ozaki N, Ishizaki M (2007) Immunohistochemical observation of amniotic membrane patching on a corneal alkali burn in vivo. Jpn J Ophthalmol 51:3–9
Rose-John S, Heinrich PC (1994) Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J 300:281–290
Zerler B (1991) The soluble interleukin-2 receptor as a marker for human neoplasia and immune status. Cancer Cells 3:471–479
McDermott MF (2001) TNF and TNFR biology in health and disease. Cell Mol Biol 47:619–635
Beresford MW (2011) Juvenile idiopathic arthritis: new insights into classification, measures of outcome, and pharmacotherapy. Paediatr Drugs 13:161–173
Na KS, Mok JW, Kim JY, Rho CR, Joo CK (2012) Correlations between tear cytokines, Chemokines, and soluble receptors and clinical severity of Dry Eye disease. Invest Ophthalmol Vis Sci 53:5443–5450
Bourke E, Cassetti A, Villa A, Fadlon E, Colotta F, Mantovani A (2003) IL-1 beta scavenging by the type II IL-1 decoy receptor in human neutrophils. J Immunol 170:5999–6005
Ambati BK, Nozaki M, Singh N, Takeda A, Jani PD, Suthar T, Albuquerque RJ, Richter E, Sakurai E, Newcomb MT, Kleinman ME, Caldwell RB, Lin Q, Ogura Y, Orecchia A, Samuelson DA, Agnew DW, St Leger J, Green WR, Mahasreshti PJ, Curiel DT, Kwan D, Marsh H, Ikeda S, Leiper LJ, Collinson JM, Bogdanovich S, Khurana TS, Shibuya M, Baldwin ME, Ferrara N, Gerber HP, De Falco S, Witta J, Baffi JZ, Raisler BJ, Ambati J (2006) Corneal avascularity is due to soluble VEGF receptor-1. Nature 443:993–997
Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L (2011) Signal transduction by vascular endothelial growth factor receptors. Biochem J 437:169–183
Acknowledgements
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).
Conflict of interest
None
Financial interest
None
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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). https://doi.org/10.1007/s00417-014-2708-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00417-014-2708-1