Signal transduction pathways for epidermal growth factor stimulated cyclooxygenase-2 induction in astrocytes.
Cyclooxygenase-2 (COX-2) derived prostaglandins (PGs) are pathophysiological mediators in various disease states. Recently, we have demonstrated the rapid, epidermal growth factor receptor (EGFR)-dependent induction of COX-2 and PGE(2) synthesis in astrocytes following optic nerve injury and in culture. We have now investigated the signal transduction pathways activated by EGFR to accomplish the expression of COX-2 in primary optic nerve astrocytes. When astrocytes were exposed to EGF, marked, rapid gene expression of COX-2 was observed. Activation of EGFR caused an increase in the phosphorylation of extracellular signal-regulated kinase (ERK), p38 MAPK (p38) and c-Jun NH (2)-terminal kinase (JNK). Furthermore, U0126, an ERK pathway inhibitor, and SB203580, a p38 MAPK inhibitor, diminished EGF-induced COX-2 expression; whereas, a JNK inhibitor did not suppress COX-2 expression by EGF. Using inhibitors of several other signaling cascades, we found that, unlike epithelial and cancer cells, NF-kappaB, PI 3-kinase/Akt and PKC were not signaling pathways for EGFR-dependent induction of COX-2 in optic nerve astrocytes. Taken together, these data suggest that ERK and p38 are key components of the intracellular signaling switch that transduces EGFR activation into COX-2 induction and PGE(2) biosynthesis in optic nerve astrocytes.
Zhang
Xu
X
Laboratory for the Investigation of the Aging Retina, Department of Ophthalmology, Northwestern University School of Medicine, Tarry 13-753, 303 East Chicago Avenue, Chicago, IL 60611, USA.
Neufeld
Arthur H
AH
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000502:physiology; D009900:Optic Nerve / Q000187:drug effects* / Q000201:enzymology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D066246:ErbB Receptors; D015232:Dinoprostone