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RS Roque, B Srinivasan, AC H Roque, AM Brun-Zinkernagel, LX Oakford, RJ Collier, MR Al-Ubaidi, S Frank; Altered Expression of Tace in Photic Injury . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3725.
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Purpose: Tumor necrosis factor-α converting enzyme (TACE), is a member of a family of transmembrane metalloproteinases involved in ectodomain shedding of growth factors and growth factor receptors from membrane-anchored precursors. Our previous finding of soluble p75NTR in the medium of degenerating photoreceptor cells and the high homology of the extracellular domain of p75NTR to that of the TACE substrate tumor necrosis factor-α receptor led us to hypothesize that p75NTR may function as a substrate for TACE. Moreover, the increased expression of p75NTR in degenerating photoreceptor cells in vivo and in vitro led us to hypothesize that TACE-induced shedding of the p75NTR extracellular domain may be involved in photoreceptor cell death. In this study, we investigated the expression of TACE in cultured photoreceptor cells and in light-damaged rat retinas, and tested the effects of TAPI, a TACE inhibitor, on photoreceptor cell survival. Methods: 661w mouse photoreceptor cells and BHR human retinal pigment epithelial (RPE) cells were exposed to light (15,000 lux) for 0-5 hrs. and assayed for cell death using neutral red or fluorescent dyes in the presence or absence of TAPI (1-50 µM). The expression of TACE and p75NTR was determined in 661w and BHR cells by immunoblot. The staining pattern for TACE was also determined in rat retinas with photic injury following 6 hrs. of blue light exposure (220fc). Results: TACE expression was upregulated in 661w cells but decreased in BHR cells following light exposure. A pattern of staining similar to that in light exposed 661w and BHR cells was observed in photoreceptor cells and RPE cells of light damaged retinas. Pretreatment of 661w cells with TAPI (1-10 µM) promoted survival in cells exposed to light for <3 hrs. Conclusion: The increased expression of TACE and p75NTR in photoreceptor cells in culture and in light-damaged retinas, and the inhibition of photoreceptor cell death by TAPI suggest that increased TACE expression and activity may be involved in photoreceptor cell death. In addition, the decreased levels of TACE in RPE cells in culture and in rat retinas following photic injury suggest that TACE may play an important role in RPE cell survival.
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