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Involvement of Protein Kinase C in TNF Regulation of Trabecular Matrix Metalloproteinases and TIMPs

From the Casey Eye Institute, Oregon Health Sciences University, Portland.

PURPOSE. The cytokine TNF is a strong modulator of trabecular meshwork (TM) matrix metalloproteinase (MMP) and tissue inhibitor (TIMP) expression. Studies were conducted to identify signal-transduction pathways involved.

METHODS. Porcine TM cells were treated with TNF, and MMP and TIMP levels were evaluated by zymography and Western immunoblot. Inhibitors and activators of several signal-transduction pathways were used to select pathways that could be involved. Trabecular protein kinase C (PKC) isoforms were identified and localized by using Western immunoblots and confocal immunohistochemistry. Changes in subcellular distribution of PKC isoforms were evaluated. PKC isoform downregulation and additional inhibition profiles were used to refine the involvement pattern of different isoforms.

RESULTS. TNF treatment increased MMP-1, -3, and -9 and TIMP-1 expression, whereas MMP-2 expression was not affected and TIMP-2 expression decreased. Agents that modulate protein kinase A (PKA) or inhibit phosphatidylinositol 3-kinase (PI3K) had minimal effects on trabecular MMP or TIMP induction by TNF, whereas several agents that modulate PKC activity were effective. Trabecular cells expressed several PKC isoforms, which exhibited distinctive subcellular localization. TNF treatment triggered some PKC isoform translocations. Exposure of trabecular cells to TNF for 72 hours differentially downregulated several PKC isoforms. Treatment with a phorbol mitogen that stimulates most PKC isoforms produced strong increases in these MMPs. TNF’s effects on MMP and TIMP expression were completely blocked by only one PKC inhibitor.

CONCLUSIONS. The PKA and PI3K pathways appear not to be involved directly in transducing this TNF signal, but at least one isoform of PKC seems to be required. Based on the inhibitor profiles and the downregulation and translocation studies, PKCµ appears to be critical in transducing this signal. Unraveling the remaining steps in this and in additional related TM signal-transduction pathways may provide targets for developing improved glaucoma treatments.

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