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Activation of the Epidermal Growth Factor Receptor in Optic Nerve Astrocytes Leads to Early and Transient Induction of Cyclooxygenase-2

From the Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri.

PURPOSE. The epidermal growth factor receptor (EGFR) appears in astrocytes after neural injury. The authors’ laboratory has reported the presence of EGFR in glaucomatous optic nerves. The activation of EGFR is often associated with induction of cyclooxygenase (COX)-2. In this study, the induction of COX-2 pathway in rat optic nerve astrocytes was investigated.

METHODS. Induction of COX-2 was determined by immunoblot and immunocytochemistry in optic nerve astrocytes stimulated with EGF. EGF-induced prostaglandin (PG)E₂ release into the culture medium was assayed by ELISA. The effects of the EGFR tyrosine kinase inhibitor, AG1478, were studied on COX-2 expression and PGE₂ synthesis. In rat optic nerve transection and a rat optic nerve explant culture model, the relationship between the expression of COX-2 and activation of EGFR was examined.

RESULTS. Activation of EGFR caused the rapid and transient induction of COX-2 in optic nerve astrocytes. The level of COX-2 was rapidly upregulated in optic nerves after axotomy and in an optic nerve explant culture model. When induced, COX-2 localized to the nuclear membrane of the astrocytes. When COX-2 was induced in response to activation of EGFR, the activated astrocytes produced and released the proinflammatory mediator, PGE₂, in a time-dependent manner. EGF-stimulated induction of COX-2 protein and synthesis of PGE₂ were abolished by the EGFR tyrosine kinase inhibitor AG1478. The stimulatory action of EGF on release of PGE₂ was inhibited by the COX-2-selective inhibitor NS398.

CONCLUSIONS. The data demonstrate that the activation of EGFR in optic nerve astrocytes leads to the induction of the immediate early gene COX-2 and subsequent signaling through the synthesis of PGE₂. This early signal of neural tissue damage may be important in setting up secondary events in the damaged tissue.

This article has been cited by other articles:

				B. Liu, H. Chen, T. G. Johns, and A. H. Neufeld Epidermal growth factor receptor activation: an upstream signal for transition of quiescent astrocytes into reactive astrocytes after neural injury. J. Neurosci., July 12, 2006; 26(28): 7532 - 7540. [Abstract] [Full Text] [PDF]