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Editors Selection IGR 11-4

Basic research: Androgen

Comment by James Lindsey on:

13748 IL-1 and TNF induction of matrix metalloproteinase-3 by c-Jun N-terminal kinase in trabecular meshwork, Hosseini M; Rose AY; Song K et al., Investigative Ophthalmology and Visual Science, 2006; 47: 1469-1476

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The induction of matrix metalloproteinase-3 (MMP-3) by trabecular meshwork following laser trabeculoplasty appears to play a key role in the resulting reduction of intraocular pressure. Although tumor necrosis factor-alfa (TNF-β) and interleukins-1β and -1β (IL-1β , IL-1β ) each may contribute to this MMP-3 induction, the signal transduction mechanisms mediating MMP-3 induction by these cytokines remains incompletely understood. To assess possible involvement of the Jun kinase-mitogen activated protein kinase (JNK-MAP) pathway, Hosseini et al. (317) exposed primary cultures of porcine trabecular meshwork cells to TNF-β , IL-1β , or IL-1β Western blots found each of the cytokines induced MMP-3 and MMP-9 release into the culture medium. These responses were inhibited by concomitant exposure to JNK inhibitor-2 (SP600125), a compound that blocks Jun kinase activity. Also, these cytokines induced activation of five additional elements of the JNK-MAP pathway, and each of these events was blocked by co-treatment with JNK-inhibitor-2. Finally, the cytokine-mediated activation of a transfected reporter gene regulated by the MMP-3 promoter was inhibited by co-transfection with a second vector coding for a dominant-negative (non-functional) mutant of JNK.

Stengths include evaluation of multiple cytokine doses, the time course studies of MMP induction and phosphorylation, as well as the clear results of the transfection experiments. A minor limitation is that only one dose of JNK inhibitor-2 (20 µM) was used. Although this dose provided greater than 97% inhibition of JNK2, it also may have partially inhibited at least two other signal transduction molecules that are not part of the JNK-MAP pathway.

These results suggest that JNK-MAP pathway activation is essential to MMP-3 release by trabecular meshwork occuring after laser trabeculoplasty. As activation of the protein kinase Cµ and the Erk mitogen-activated pathways also are essential, the present results suggest triggering of all three signaling pathways is required. These results may facilitate the development of drug treatments that mimic the beneficial effects of laser trabeculoplasty.

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