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Synergism of TNF and IL-1 in the Induction of Matrix Metalloproteinase-3 in Trabecular Meshwork

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

PURPOSE. TNF and IL-1 increase matrix metalloproteinase-3 (MMP-3) expression in the trabecular meshwork (TM). TNF-, in combination with IL-1 or IL-1ß, produces highly synergistic MMP-3 increases. Possible mechanisms for this synergism in TM cells were investigated.

METHODS. Porcine and human TM cells were treated with TNF-, IL-1, IL-1ß and their combinations. Western immunoblots were used to evaluate MMP-3, MMP-9, MMP-12, TNF-, IL-1, IL-1ß, IL-6, TNF receptor I (RI), IL-1 RI, and IL-1 RII levels and the phosphorylation of Erk, JNK, and p38 MAP kinases. Dose–response effects for TNF-, IL-1 and IL-1ß on MMP-3 were evaluated. Microarray and quantitative RT-PCR were used to determine mRNA levels. MMP-3 transcription rate was assessed by transfecting TM cells with an MMP-3 promoter/reporter construct. Combined cytokine effects on outflow facility were appraised in perfused anterior segment organ culture.

RESULTS. TNF-, IL-1, and IL-1ß each individually increased MMP-3 levels, whereas TNF- in combination with IL-1 or IL-1ß produced highly synergistic increases. MMP-9 and MMP-12 levels were also elevated, but only MMP-12 showed synergism. IL-1, IL-1ß, and IL-6, but not TNF- mRNA or protein level, were elevated by these cytokines. Maximum MMP-3 production for individual cytokines, even at high doses, was far less than with dual cytokine doses. Erk 1 and 2, JNK 1 and 2, and p38 and ß phosphorylation increased, but not synergistically. However, phosphorylation of novel isoforms of JNK and p38 and did show synergism. MMP-3 mRNA levels and transcription rates also demonstrated synergism. TNF- significantly increased IL-1 RI levels. Synergism in outflow facility was observed with TNF- and IL-1.

CONCLUSIONS. TNF-, in combination with IL-1 or IL-1ß, produced intense synergistic increases in MMP-3 and MMP-12 but not in MMP-9. Induction of IL-1 RI by TNF- partially explains the synergism. Responses of novel JNK and p38 MAP kinase and isoforms also partially account for the synergism. Understanding this strong synergistic effect may provide useful insight into optimizing therapeutic regulation of intraocular pressure in glaucoma.

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