May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Pro-Inflammatory Cytokines Increase Retinal Endothelial Cell Permeability: Protective Effect of Dexamethasone
Author Affiliations & Notes
  • C. A. Aveleira
    Center of Ophthalmology, IBILI Faculty of Medicine University of Coimbra, Coimbra, Portugal
  • E. B. Wolpert
    C&M Physiology, PSU College of Medicine, Hershey, Pennsylvania
  • A. F. Ambrosio
    Center of Ophthalmology, IBILI Faculty of Medicine University of Coimbra, Coimbra, Portugal
  • D. A. Antonetti
    C&M Physiology, PSU College of Medicine, Hershey, Pennsylvania
  • Footnotes
    Commercial Relationships  C.A. Aveleira, None; E.B. Wolpert, None; A.F. Ambrosio, None; D.A. Antonetti, None.
  • Footnotes
    Support  FCT (SFRH/BD/18827/2004), Portugal, FEDER, and NIH Grant EY012021, the Juvenile Diabetes Research Foundation and a Grant from Allergan
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 2649. doi:https://doi.org/
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      C. A. Aveleira, E. B. Wolpert, A. F. Ambrosio, D. A. Antonetti; Pro-Inflammatory Cytokines Increase Retinal Endothelial Cell Permeability: Protective Effect of Dexamethasone. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2649. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Diabetic retinopathy has characteristics of a low-grade chronic inflammatory disease. Interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α) increase in the vitreous of diabetic patients and in diabetic rat retinas commensurate with elevated retinal vascular permeability. Inflammatory cytokines, particularly TNF-α, may induce endothelial cell apoptosis that could alter the blood-retinal barrier (BRB). Alternatively, these cytokines may signal alterations to the junctional complex increasing permeability. In this study, the mechanism by which IL-1β and TNF-α induce retinal endothelial cell permeability was investigated. Further, the ability of the glucocorticoid, dexamethasone (DEX), to prevent cytokine-induced permeability was determined.

Methods: : Primary cultures of bovine retinal endothelial cells (BRECs) were grown on transwell filters and exposed to IL-1β and TNF-α. BRECs permeability to 70 kDa RITC-dextran was measured. Dose-response and time-course experiments were performed in order to assess and compare the effectiveness of IL-1β and TNF-α to increase cell permeability. Western blotting and immunocytochemistry for tight junction proteins were performed to determine their content and localization.

Results: : Both IL-1β and TNF-α significantly increased retinal endothelial cell permeability in a dose- and time-dependent manner. The effect of TNF-α on cell permeability was relatively rapid, reaching significance by 6 h, whereas IL-1β treatment increased cell permeability by 24 h. The effects of IL-1β and TNF-α on cell permeability were not due to cell death. Immunocytochemistry demonstrated that TNF-α altered ZO-1 border staining and Western blotting suggested a decrease in ZO-1 content. DEX pre-treatment for 6 h and 24 h prevented TNF-α-induced cell permeability.

Conclusions: : These results demonstrate that IL-1β and TNF-α increase retinal endothelial cell permeability and that TNF-α is a particularly potent permeabilizing agent. TNF-α treatment decreases ZO-1 content and disrupts ZO-1 organization at cell borders with no change in cell viability. DEX treatment completely prevents the TNF-α-induced increase in retinal endothelial cell permeability. These data demonstrate that TNF-α and IL-1β potently induce endothelial permeability independent of cell death, potentially through alterations in the tight junction complex. Moreover, the study supports the potential therapeutic use of DEX to reduce retinal vascular permeability.

Keywords: diabetic retinopathy • signal transduction • inflammation 
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