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IL-1 and TNF Induction of Matrix Metalloproteinase-3 by c-Jun N-Terminal Kinase in Trabecular Meshwork

¹From the Casey Eye Institute, Oregon Health & Science University, Portland, Oregon; and ²Triple Point Biologics, Forest Grove, Oregon.

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 TNF, IL-1, or IL-1ß. 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 TNF or IL-1 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 TNF and IL-1 induction of MMP-3 expression was then evaluated.

RESULTS. TNF, IL-1, and IL-1ß 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 TNF and IL-1 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 TNF, IL-1, or IL-1ß 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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