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Mary J. Kelley, Anastasia Rose, Kaili Song, Barbara Lystrup, John W. Samples, Ted S. Acott; p38 MAP Kinase Pathway and Stromelysin Regulation in Trabecular Meshwork Cells. Invest. Ophthalmol. Vis. Sci. 2007;48(7):3126-3137. doi: 10.1167/iovs.06-1375.
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purpose. Increased expression of stromelysin-1 (matrix metalloproteinase [MMP]-3) by the trabecular meshwork (TM) initiates extracellular matrix turnover and increases aqueous humor outflow facility. Tumor necrosis factor (TNF)α and interleukin (IL)-1α are efficacious inducers of MMP-3 in TM. To facilitate understanding of the regulation of MMP-3, the authors investigated the involvement of p38 MAP kinase pathway proteins in this process.
methods. Western immunoblots were used to determine the effects of these cytokines and p38 MAP kinase pathway inhibitors on MMP-3 protein levels, p38 MAP kinase isoforms, and phosphorylation levels in human and porcine TM cells. The effects of a dominant-negative p38 MAP kinase construct on MMP-3 expression were evaluated. Morphologic changes in the cells were also examined.
results. Both cytokines increased MMP-3 levels. The p38 MAP kinase inhibitor SB202190 diminished MMP-3 induction by TNFα at all times and at 24 hours by IL-1α but potentiated the IL-1α–induced increase in MMP-3 at later times. MMP-3 induction by both cytokines was blocked by dominant-negative p38 MAP kinase constructs. Each cytokine increased phosphorylation of the p38 MAP kinase pathway components and altered TM cell morphology. The p38 inhibitor blocked only the morphologic changes produced by TNFα. Human and porcine TM cells expressed p38 α, β, δ, and γ isoforms, which migrate coincident with bands of specific phosphorylation.
conclusions. The effects of p38 inhibitors and the dominant-negative construct on TNFα and IL-1α induction of MMP-3 demonstrate an essential role for p38 in this signaling process. Differences between p38 inhibitor effects on TNFα and IL-1α induction of MMP-3 suggest divergent p38 isoform use, as do the morphologic responses. The anomalous p38 inhibitor effect on IL-1α induction of MMP-3 and phosphorylation of p38 δ/γ suggests complex interactions between p38 MAP kinase isoforms and their differential uses by TNFα and IL-1α in TM.
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