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Infliximab counteracts tumor necrosis factor-α-enhanced induction of matrix metalloproteinases that degrade claudin and occludin in non-pigmented ciliary epithelium.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 2013 Jun 15; Vol. 85 (12), pp. 1770-82. Date of Electronic Publication: 2013 Apr 16. - Publication Year :
- 2013
-
Abstract
- Infliximab, a monoclonal antibody directed against human tumor necrosis factor-alpha (TNF-α), effectively treats anterior uveitis, which can accompany Behçet'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 TNF-α using quantitative, real-time polymerase chain reaction and enzyme-linked immunosorbent assays. The expression of MMP-1, MMP-3, and MMP-9 increased in the presence of TNF-α, and the addition of infliximab reversed the increase. The TNF-α effects were more attenuated when infliximab was added before than when it was added after TNF-α exposure. Gelatin zymography demonstrated that the protease activity of these MMPs was also increased in the presence of TNF-α 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-α 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-α-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.<br /> (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cells, Cultured
Ciliary Body drug effects
Claudin-1 metabolism
Down-Regulation drug effects
Down-Regulation immunology
Enzyme Induction drug effects
Enzyme Induction physiology
Epithelial Cells drug effects
Epithelial Cells metabolism
Humans
Infliximab
Matrix Metalloproteinase Inhibitors metabolism
Matrix Metalloproteinase Inhibitors toxicity
Matrix Metalloproteinases biosynthesis
Occludin metabolism
Swine
Antibodies, Monoclonal pharmacology
Ciliary Body metabolism
Claudin-1 antagonists & inhibitors
Matrix Metalloproteinases metabolism
Occludin antagonists & inhibitors
Tumor Necrosis Factor-alpha antagonists & inhibitors
Tumor Necrosis Factor-alpha toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2968
- Volume :
- 85
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 23603294
- Full Text :
- https://doi.org/10.1016/j.bcp.2013.04.006