Optic Nerve Ligation-Induced Interleukin-1 Beta Through MAP Kinase Mediates MMP-9 Induction and Retinal Damage

Abstract

Abstract: : Purpose: We previously have shown that optic nerve ligation-induced ganglion cell loss was associated with matrix metalloproteinase-9 (MMP-9) induction in the retina. The objective of the present study was to determine whether optic nerve ligation-induced interleukin-1 beta (IL-1ß) through mitogen activated protein (MAP) kinases cause induction of MMP-9 and subsequent retinal damage. Methods: Retinal ganglion cell loss in CD-1 mice was induced by optic nerve ligation. Retinal proteins from control and optic nerve ligated retinas were extracted three hours to 1 week after optic nerve ligation, and IL-1ß levels were determined using an ELISA kit. MAP Kinase activation and MMP-9 synthesis was determined by western blot analysis. Retinal morphology was assessed by Hematoxylin & Eosin staining. Results: Optic nerve ligation led to progressive loss of ganglion cells in the retina. Compared to controls, IL-1ß levels were increased as early as 12h, reached a peak by day 2, and returned to undetectable levels by day 6. Peak IL-1ß levels observed 2 days after optic nerve ligation were associated with induction of phosphorylated p44/42 MAPK/extracellular signal-regulated kinase (Erk1 and Erk2) and MMP-9 synthesis. Compared to controls, no change in p38 MAP kinase and c-jun N-terminal kinase was observed after optic nerve ligation. Intravitreal injection of IL-1 receptor antagonist (10 ng) or U0126 (200 nM), a MAP kinase kinase (MEK) inhibitor 10 min before optic nerve ligation resulted in reduced Erk1 and Erk2 activation 2 days after optic nerve ligation. Finally, optic nerve ligation-induced peak expression of MMP-9 synthesis at day 2 was reduced by intravitreal injection of IL-1 receptor antagonist, followed by reduced retinal ganglion cell loss by 1 week. Conclusions: These results suggest that optic nerve ligation-induced IL-1ß through MEK and its down stream target ERK1/2 kinase mediates MMP-9 induction in the retina and plays an important role in retinal damage.

Keywords: ischemia • retina • ganglion cells