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Mojgan Hosseini, Anastasia Y. Rose, Kaili Song, Cynthia Bohan, J. Preston Alexander, Mary J. Kelley, Ted S. Acott; IL-1 and TNF Induction of Matrix Metalloproteinase-3 by c-Jun N-Terminal Kinase in Trabecular Meshwork. Invest. Ophthalmol. Vis. Sci. 2006;47(4):1469-1476. doi: 10.1167/iovs.05-0451.
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purpose. The cytokines TNF and IL-1 mediate the MMP-3 increase that occurs in response to trabecular meshwork (TM) treatment by laser trabeculoplasty. This MMP-3 increase appears to play a key role in the efficacy of this treatment for open-angle glaucoma. Protein kinase Cμ and the Erk mitogen-activated protein (MAP) kinases are essential signaling components in transducing MMP-3 increases produced by treatment of TM cells with these cytokines. Here, the involvement of the JNK-MAP kinase pathway in this process was evaluated.
methods. Porcine TM cells were treated with TNFα, IL-1α, or IL-1β. Changes in MMP-3 and MMP-9 protein levels in the media were then determined by Western immunoblot. The effect of JNK inhibitor 2 was evaluated. Changes in the level of phosphorylation of JNK, c-Jun, ATF-2, MKK4, and MKK7 were also determined at various times after TNFα or IL-1α treatment. A 2.3-kb MMP-3 promoter fragment was cloned into a secreted alkaline phosphatase reporter vector. This reporter construct was cotransfected into TM cells with a mammalian expression vector containing a dominant-negative mutant of JNK. The involvement of JNK activity in the TNFα and IL-1α induction of MMP-3 expression was then evaluated.
results. TNFα, IL-1α, and IL-1β increase media MMP-3 and MMP-9 protein levels, and JNK inhibitor 2 blocks these increases. JNK1/2, MKK4, c-Jun, and ATF-2 phosphorylation levels increase in response to TNFα and IL-1α treatment. JNK inhibitor 2 pretreatment blocks these c-Jun and ATF-2 phosphorylation increases. Dominant-negative JNK dramatically reduces the MMP-3 promoter–driven reporter activity induced by these cytokines.
conclusions. JNK activity is necessary for the induction of MMP-3 and MMP-9 by TNFα, IL-1α, or IL-1β in TM cells. Phosphorylation of components of the JNK signaling pathway and of the transcription factors c-Jun and ATF-2 support a role for this pathway in the induction of MMP-3 and MMP-9 in the TM in response to these cytokines. Thus, at least three separate signal transduction pathways are necessary in this signaling event in TM cells.
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