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

Abstract

Abstract: : Purpose: The epidermal growth factor receptor (EGFR) appears in astrocytes following neural injury. Our laboratory has previously reported the presence of EGFR in glaucomatous optic nerves. Because activation of EGFR is often associated with induction of COX–2, we have investigated this pathway in rat optic nerve astrocytes. Methods: Induction of COX–2 was determined by immunoblot and immunocytochemistry in optic nerve astrocytes stimulated with EGF. EGF–induced PGE₂ release into the culture media was assayed by ELISA. The effects of the EGFR tyrosine kinase inhibitor, AG1478, were studied on COX–2 expression and PGE₂ synthesis. Using rat optic nerve transection and a rat optic nerve explant culture model, we examined the relationship between the expression of COX–2 and activation of EGFR. Results: We found that activation of EGFR causes the rapid and transient induction of COX–2 in optic nerve astrocytes. We also found that 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 localizes to the nuclear membrane of the astrocytes. When COX–2 is induced in response to activation of EGFR, the activated astrocytes produce and release the proinflammatory mediator, PGE₂, in a time–dependent manner. EGF stimulated induction of COX–2 protein and synthesis of PGE₂ was abolished by the EGFR tyrosine kinase inhibitor, AG1478. The stimulatory action of EGF on PGE₂ release was inhibited by the COX–2 selective inhibitor, NS398. Conclusions: Our 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.

Keywords: astrocytes: optic nerve head • neuroprotection