Influence of interleukin-1 beta induction and mitogen-activated protein kinase phosphorylation on optic nerve ligation-induced matrix metalloproteinase-9 activation in the retina.
Ischemic damage to the retina is a multifaceted process that results in irreversible loss of ganglion cells and blinding disease. Although the mechanisms underlying ischemia-induced ganglion cell death in the retina are not clearly understood, we have recently reported that retinal damage induced by ligation of the optic nerve results in increased matrix metalloproteinase-9 (MMP-9) synthesis and promotes ganglion cell loss. In this study, we have investigated the roles of IL-1beta and mitogen activated protein kinases in MMP-9 induction in the retina. Optic nerve ligation led to a transient increase in IL-1beta and MMP-9 levels and phosphorylation of p42/p44 mitogen activated protein kinases (extracellular signal-regulated kinases, ERK1 and ERK2) in the retina. We found no significant increase in phosphorylation of p38 MAP kinase or c-jun N-terminal kinases indicating that ERK1/2 plays a major role in MMP-9 induction. Intravitreal injection of IL-1 receptor antagonist (IL-1Ra) or MAP kinase inhibitor U0126 significantly decreased both ERK1/2 phosphorylation and MMP-9 induction suggesting that interruption of this cascade might attenuate retinal damage. In support of this, intravitreal injection of IL-1Ra and U0126 offered significant protection against optic nerve-induced retinal damage. These results suggest that optic nerve ligation-induced IL-1beta promotes retinal damage by increasing MMP-9 synthesis in the retina.
Zhang
Xu
X
Eye Research Institute, Oakland University, 409 Dodge Hall, Rochester, MI 48309, USA.
Chintala
Shravan K
SK
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002070:Butadienes / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007375:Interleukin-1 / Q000276:immunology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D018917:Optic Neuropathy, Ischemic / Q000201:enzymology*; D010766:Phosphorylation; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D012160:Retina / Q000201:enzymology*
D002070:Butadienes; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D009570:Nitriles; D017472:Receptors, Interleukin-1; C113580:U 0126; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9