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Payton Russom, Cathryn Formichella, Rebecca Sappington; Cleavage of IL-6 receptor alpha as a potential mechanism for IL-6 transsignaling in Glaucoma. Invest. Ophthalmol. Vis. Sci. 2013;54(15):786.
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Previous work suggests that interleukin-6 (IL-6) signaling via both classical and transsignaling pathways may be important for retinal ganglion cell survival (RGC) in glaucoma. Here we evaluate the possibility that IL-6 transsignaling is mediated by cleavage of membrane-bound IL-6 receptor alpha (IL-6Rα) by metalloproteinases ADAM10 and ADAM17.
Using immunolabeling and immunoblotting, we examined the expression and localization patterns of ADAM10 and ADAM17 in whole eye paraffin sections and protein lysates from glaucomatous DBA/2 and control C57 mice. We then perfomred co-localization studies to compare expression and localization patterns of ADAM10 and ADAM17 and their potential target, IL-6Rα. Cell type-specific markers were used to confirm retinal ganglion cell (β-tubulin), rod bipolar cell (PKCα) and Muller glial cell (glutamine synthetase) identities.
We found that both ADAM10 & ADAM17 are expressed in healthy and glaucomatous retina, where they localize to multiple layers. Co-immunolabeling revealed that ADAM10 and ADAM17 are primarily expressed by RGCs, which also express IL-6Rα. Quantification of ADAM10 and ADAM17 expression in the ganglion cell and nerve fiber layers of retina revealed that while ADAM10 expression did not change significantly with age (p > 0.05) or IOP (p > 0.05), elevated IOP increased ADAM17 expression by up to 55% (p = 0.03). There was no age-related increase in ADAM17 expression (p > 0.05).
Our data suggests that the necessary machinery (ADAM 10 & ADAM 17) is present in RGCs to cleave existing membrane-bound IL-6Rα into soluble IL-6R. Interestingly, elevated IOP only altered the expression ADAM17 by RGCs. This suggests that ADAM17, in particular, may be a mechanism for the induction of IL-6 transsignaling in glaucoma.
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