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A.R. Mason, S. Husain, A.V. Tkatchenko, J. Fant, C.E. Crosson; Dexamethasone–Induced Upregulation of Mitogen–Activated Protein Kinase Phophatase–1 (MKP–1) in the Human Trabecular Meshwork Cells . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3689.
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Purpose: The chronic administration of steroids can increase IOP; however, the cellular mechanisms responsible for this rise in IOP are not understood. The purpose of these studies was to investigate how exposure of human trabecular cells to dexamethasone alters MAP kinase signaling in these cells. Methods: Cultured primary human trabecular meshwork and ciliary smooth muscle cells were incubated in the presence or absence of dexamethasone (1 µmol/L) for 24 to 48 hours. The expression and activation of ERK was determined by western blot analyses. The expression of dual specific phosphatases, MKP–1 and MKP–3, were determined by quantitative real–time PCR and Western blot analysis. Results: The addition of dexamethasone for 24 or 48 hours did not alter the expression of ERK protein; however, the activation (i.e., phosphorylation) of this kinase by serum was inhibited by 70%. In cells treated for 24 or 48 hours with dexamethasone MKP–1, mRNA expression was increased over 6–fold. MPK–1 protein expression was also significantly enhanced by dexamethasone treatment. The addition of dexamethasone produced only a modest increase of 71% in the expression of MKP–3 mRNA. In human ciliary muscle cells, the addition of dexamethasone for 24 hours produced only a 30 to 40% increase in MKP–1 mRNA and no measurable change in MKP–3 mRNA. Conclusions: These studies demonstrate that exposure of trabecular meshwork cells to dexamethasone inhibits ERK signaling. This inhibition did not involve a decrease in expression of ERK. However, dexamethasone did induce over a 6–fold increase in the dual specific phosphatases MKP–1, which is responsible for the dephosphorylation (i.e., inactivation) of ERK. Dexamethasone produced little or no upregulation of MKPs in ciliary muscle cells. These results provide evidence that steroid–induced glaucoma may in part result from a cell–specific upregulation of MKP–1 in trabecular meshwork cells resulting in the dysregulation of MAP kinase signaling in these cells.
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