Journal
BIOCHEMICAL PHARMACOLOGY
Volume 85, Issue 12, Pages 1770-1782Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2013.04.006
Keywords
Tumor necrosis factor-alpha (TNF-alpha); Infliximab; Matrix metalloproteinase (MMP); Non-pigmented ciliary epithelial cells; Blood aqueous barrier (BAB)
Categories
Funding
- Strategic Research Foundation Grant for the aid of Projects in Private Universities
- Ministry of Education, Culture, Sports, Science, and Technology, Japan (MEXT) [S1101027]
- [22591953]
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Infliximab, a monoclonal antibody directed against human tumor necrosis factor-alpha (TNF-alpha), effectively treats anterior uveitis, which can accompany Behcet's disease. Here, we investigated the underlying mechanism of this action. We examined human, non-pigmented ciliary epithelial cells (HNPCECs), which make up the blood aqueous barrier (BAB) in the uvea. We measured the expression levels of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the presence or absence of TNE-alpha using quantitative, real-time polymerase chain reaction and enzyme-linked immunosorbent assays. The expressioa of MMP-1, MMP-3, and MMP-9 increased in the presence of TNF-alpha, and the addition of infliximab reversed the increase. The TNF-alpha effects were more attenuated when infliximab was added before than when it was added after TNF-alpha exposure. Gelatin zymography demonstrated that the protease activity of these MMPs was also increased in the presence of TNF-alpha and attenuated with infliximab. Immunostaining showed that MMP-1, MMP-3, and MMP-9 degraded claudin-1 and occludin in HNPCECs and in non-pigmented ciliary epithelial cells of the swine ciliary body. In a monolayer of HNPCECs, we found that permeability was significantly increased with MMP treatment. Thus, TNF-alpha increased levels of MMPs in cells that form the BAB, and MMPs degraded components of the tight junctions in the BAB, which increased permeability through the cellular barrier. Furthermore, infliximab effectively attenuated the TNF-alpha-induced increases in MMP expression in cells that make up the BAB. These findings might suggest a basis for the clinical prevention of anterior uveitis. (C) 2013 Elsevier Inc. All rights reserved.
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