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Naseem Akhter, Melissa Nix, Yasir Abdul, Sudha Singh, Shahid Husain; Delta-Opioid Receptors Attenuate TNF-α–Induced MMP-2 Secretion From Human ONH Astrocytes. Invest. Ophthalmol. Vis. Sci. 2013;54(10):6605-6611. doi: https://doi.org/10.1167/iovs.13-12196.
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We examined the signaling mechanisms involved in δ-opioid–receptor agonist, SNC-121–mediated attenuation of TNF-α–induced matrix metalloproteinase-2 (MMP-2) secretion from human optic nerve head (ONH) astrocytes.
Human ONH astrocytes were treated with SNC-121 (1 μmol/L) for 15 minutes followed by TNF-α (25 ng/mL) treatment for 6 or 24 hours. Cells were pretreated with inhibitors of p38 mitogen-activated protein (MAP) kinase (SB-203580) or NF-κB (Helenalin) prior to TNF-α treatment. Changes in phosphorylation and expression of p38 MAP kinase, IκBα, NF-κB, and MMP-2 were measured by Western blotting. Translocation of NF-κB was determined by immunocytochemistry.
TNF-α treatment increased MMP-2 secretion from ONH astrocytes to 236% ± 17% and 142% ± 8% at 6 and 24 hours, respectively; while SNC-121 treatment reduced MMP-2 secretion to 149% ± 11% and 108% ± 7% at 6 and 24 hours, respectively. The SNC-121-mediated inhibitory response was blocked by the δ-opioid–receptor antagonist naltrindole. TNF-α treatment resulted in a sustained phosphorylation of p38 MAP kinase up to 24 hours (226% ± 15% over control levels), which was reduced to 150% ± 20% by SNC-121 treatment. TNF-α treatment increased the expression of NF-κB to 179% ± 21% and 139% ± 6% at 6 and 24 hours, respectively, which was significantly blocked by SNC-121 treatment. Furthermore, TNF-α–induced MMP-2 secretion was blocked by 100% and 78% in the presence of SB-203580 and Helenalin, respectively.
Evidence is provided that SNC-121 attenuated TNF-α–induced MMP-2 secretion from ONH astrocytes. Data also supported the idea that p38 MAP kinase and NF-κB played central roles in TNF-α–induced MMP-2 secretion, and both were negatively regulated by SNC-121.
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