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(Investigative Ophthalmology and Visual Science. 2003;44:164-169.)
© 2003 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.01-1201
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Involvement of the Erk-MAP Kinase Pathway in TNF{alpha} Regulation of Trabecular Matrix Metalloproteinases and TIMPs

J. Preston Alexander and Ted S. Acott

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

PURPOSE. TNF{alpha} is a strong modulator expression of trabecular meshwork (TM) matrix metalloproteinase (MMP) and tissue inhibitor (TIMP). Laser trabeculoplasty appears to rely on this process to restore normal aqueous humor outflow facility. Thus, studies were conducted to determine whether the extracellular signal-regulated kinase (Erk)-mitogen-activated protein (MAP) kinase signal-transduction pathway is involved.

METHODS. Porcine TM cells were treated with TNF{alpha}, and changes in MMPs and TIMPs were evaluated by zymography and Western immunoblot assay. Phosphospecific antibodies to proteins from the Erk pathway were used to evaluate responses to treatment with TNF{alpha}. Inhibitors of Mek, the kinase that activates Erk, and of protein kinase C (PKC) isoforms were used to define pathway involvement.

RESULTS. Treatment with TNF{alpha} increased MMP-1, -3, and -9 and TIMP-1, whereas expression of MMP-2 was not affected and expression of TIMP-2 was decreased. Erk and Mek were rapidly phosphorylated after treatment with TNF{alpha}, and c-Raf-1 showed a significant bandshift. A specific inhibitor of Mek blocked the TNF{alpha} induction of the MMPs and TIMPs and the phosphorylation of Erk. An inhibitor of the PKC-µ isoform, which also blocks the effects of MMP-TIMP of TNF{alpha}, did not affect phosphorylation of Erk.

CONCLUSIONS. The components of this MAP kinase pathway in the TM are dramatically affected by TNF{alpha} and inhibition of Erk’s phosphorylation blocks the changes in MMP and TIMP expression. PKC µ, which is also required in this transduction process, does not appear to be upstream from Erk in the signaling cascade. Manipulation of this and related TM signal-transduction pathways may provide targets for developing improved glaucoma treatments.




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