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M. Hosseini, A.Y. Rose, M.J. Kelley, T.S. Acott; IL1 Regulation of Trabecular Meshwork Matrix Metalloproteinases via the JNK–MAP Kinase Pathway . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1344.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: IL–1α is a strong modulator of expression of trabecular meshwork (TM) matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Increased activity of MMPs restores normal aqueous outflow facility after laser trabeculoplasty, a common treatment for glaucoma. Studies were conducted to determine the role of the jun N–terminal kinase (JNK) pathway in this process. Methods: Porcine trabecular meshwork cells (TM) were treated with recombinant human IL–1α at 25ng/ml for 5, 10, 15, 30 and 60 minutes, 4 and 24 hours. Western immunoblot analysis was used to examine the phosphorylation levels of MKK4 (Ser257/The261), JNK (Thr183/Tyr185), c–jun (Ser63/Ser73) and ATF–2 (Thr71). The effects of pretreatment with JNK inhibitor II or with inhibitors of Erk1/2 activation, PD98059 or U0126, on the IL–1α response were also analyzed. Results: IL–1α induces myocilin and MMP–3 in TM cells. IL–1α treatment significantly increases the phosphorylation and thus activation levels of MKK4, JNK, c–jun and ATF–2 in a time dependent manner. MKK4 and JNK are phosphorylated at 15 minutes and remain active for an hour. Protein and phosphorylation levels for c–jun are increased at 60 minutes post–treatment, while ATF–2 is phosphorylated at 10 minutes and stays active for an hour. Western blot analysis shows inhibition of c–jun and reduction of ATF–2 phosphorylation upon treatment with JNK inhibitor II, PD98059 or U0126. Inhibiting JNK blocks IL–1α induction of myocilin and MMP–3 in TM cells. Conclusions: IL–1α treatment plays a significant role in activation of the jun N–terminal kinase pathway in TM cells. IL–1α effects on the JNK pathway are similar to those of TNF–α treatment. The downstream effect of IL–1α or TNF–α treatment is increased expression of the MMPs that regulate intraocular pressure. Elucidation of the signaling pathways through which IL–1α effects are transmitted could lead to new treatments for glaucoma.
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