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M.E. Fini, X. Zhang, N. Wang, S. Diskin, K.A. Erickson, J.S. Schuman; Glaucomatous Trabecular Meshwork Cells are Unresponsive to Treatment with Exogenous Interleukin-1 . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3167.
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Purpose: We recently described an autocrine IL-1-regulated cellular stress response specific to the eye's aqueous outflow pathways that is diagnostic of glaucomas of diverse etiology (Nat. Med. 2001; 7:304-309). This pathway is protective in the short run, but in the long run may lead to disease. The goal of this study was to further define IL-1-regulated signaling pathways in normal TM cells and determine whether their activity is altered in glaucomatous TM cells. Methods: Primary cultures of normal or glaucomatous trabecular meshwork (TM) cells were established from tissues derived from cadaver eyes or trabeculectomy specimens. Cells were treated with exogenous IL-1alpha at 10 ng/ml and phosphorylated (activated) forms of the protein kinases ERK1/2, JNK1, JNK2, and P38 was quantified by western blotting and densitometry over a one hour time course. Results: Active forms of ERK1/2, JNK1, and P38 could be detected in all normal and glaucomatous cell lines examined prior to treatment with IL-1alpha. However, the level was consistently higher in the glaucomatous (N=5) as compared to the normal cell lines (N=5). Treatment of cells derived from normal eyes with exogenous IL-1 stimulated an increase in the activation of each kinase. This change was first detectable within five minutes, peaked between ten and thirty minutes, then decreased. In contrast, IL-1 treatment of TM cells derived from glaucomatous eyes stimulated little or no change in kinase activation. Activated levels of JNK2 could be detected in only one normal and one glaucomatous cell line, but the trend of change in response to IL-1 was the same as for the other kinases. ELAM-1, a gene downstream of IL-1 signaling, was not expressed by normal TM cells, but was constitutively expressed by glaucomatous cells. Treatment with exogenous IL-1 stimulated ELAM-1 expression in normal cells, but did not increase the expression level in glaucomatous TM cells. Conclusions: Glaucomatous TM cells are unable to adapt to changes in extracellular levels of IL-1. Selective down-regulation of the IL-1-regulated signaling pathways using inhibitors of ERK, JNK, or P38 might serve to modulate this situation, and may thus affect the development and progression of glaucomatous optic neuropathy.
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