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M. Hosseini, M.J. Kelley, T.S. Acott; The Regulation of Myocilin Expression Through the JNK Pathway in Porcine Trabecular Meshwork Cells . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1164.
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Purpose: To determine the role of the JNK-MAP kinase pathway in the regulation of myocilin production in trabecular meshwork cells. Methods: Porcine trabecular meshwork cells were subjected to 10% mechanical stretch, TNFα (10 ng/ml) or IL-1α (10-25 ng/ml) treatment with or without JNK inhibitor II (20-30 µM) for 24, 48 and 72 hours. Western immunoblot analysis was used to examine the effect of JNK inhibitor II on S63 and S73 c-jun phosphorylation as well as a time course of myocilin expression. Results: Mechanical stretch, TNFα and IL-1α treatment all significantly increase the production and secretion of myocilin into the culture medium. Much of the secreted myocilin is the 65 kDa glycosylated form but the 55 kDa non-glycosylated form, the 75 kDa aggregate, and a 37 kDa proteolyzed form were also present with and without treatment. Inhibiting JNK completely blocks TNFα induction of myocilin, whereas it only partially blocks IL-1α induction. Western blot studies show a reduction in c-jun phosphorylation at S63 and S73 when cells are treated with JNK inhibitor II. Conclusions: The data suggest that more than one pathway controls the expression of myocilin and that TNFα induction of this protein requires JNK activity. Mechanical stretch and IL-1α, however, may use other pathways as well as the JNK-MAP kinase pathway. Further illumination of the various myocilin production pathways may provide insights into how this protein functions in normal and glaucomatous eyes.
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