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K. V. Ramana, N. M. Kalariya, S. Mohammad, A. B. M. Reddy; Inhibition of Tumor Necrosis Factor Converting Enzyme (TACE) Prevents Endotoxin-Induced Uveitis In Rats. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4830.
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Tumor necrosis factor (TNF)-α converting enzyme (TACE) processed ectodomain shedding of inflammatory cytokines especially TNF-α, has been shown to mediates a number of inflammatory pathologies including rheumatoid arthritis, Crohn's disease and cancer. However, it is not known how TACE mediated ectodomain shedding of TNF-α in ocular system that contributes to ocular inflammatory diseases such as uveitis. Hence present study was performed to investigate the effect of TACE inhibition in endotoxin-induced uveitis (EIU) in rats.
To examine effect of TACE inhibition on ocular inflammation in vivo, we have investigated rodent model of EIU in the absence and presence of TACE inhibitor, TAPI-1. EIU was developed in Lewis rats by subcutaneous injection of LPS (150 ug/rat). The rats were sacrificed at 24 h after LPS injection, and eyes were enucleated and aqueous humor was collected immediately. The number of infiltrating cells, protein concentration, and the levels of inflammatory markers were determined in the aqueous humor. Immunohistochemical analysis was performed in sections of rat eyes to examine the expression of various inflammatory markers and activation of NF-ΚB.
Inhibition of TACE significantly prevents infiltration of inflammatory cells and increased levels of inflammatory markers such as nitric oxide, TNF-α, PGE2 and Cox-2 in the aqueous humor of EIU rats. TACE inhibition also significantly suppressed generation of ROS, activation of NF-ΚB and expression of inflammatory markers in various ocular tissues of EIU rat eyes. Inhibition of TACE also prevented LPS-induced TACE -mediated ectodomain shedding of TNF-α in human ciliary epithelial cells.
Our results provide pivotal role of TACE in mediating ocular inflammatory signals and suggest the use of TACE inhibition as a novel therapeutic approach to prevent ocular inflammation.
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