Regulation of retinal glial cell proliferation by antiproliferative molecules.
Glial cells normally do not proliferate in the adult retina despite the presence of glial mitogens. In this study, we examined the hypothesis that endogenous antiproliferative molecules inhibit the effects of glial mitogens. Using cultures of glial cells obtained from the adult human retina, we found that transforming growth factor beta 2 (TGF beta 2) and a metabotrophic glutamate agonist (t-ACPD) inhibit the mitogenic effects of basic fibroblast growth factor, platelet-derived growth factor, epidermal growth factor and insulin-like growth factor-1. These antiproliferative effects may involve activation of protein kinase C (PKC) since chelerythine, a specific PKC inhibitor, blocks the antiproliferative effects of TGF beta 2 and t-ACPD. Furthermore, exposure of the glia to a phorbol ester mimics the inhibitory effects of TGF beta 2 or t-ACPD. Although TGF beta 2 and t-ACPD markedly inhibit a number of mitogens, they do not alter the mitogenic response of retinal glia to thrombin and glutamate. A common characteristic of the mitogens sensitive to TGF beta 2 or t-ACPD is activation of tyrosine kinase-linked receptors. In contrast, thrombin acts at a G-protein-linked receptor, and glutamate stimulates retinal glial proliferation via activation of an NMDA receptor. It appears that TGF beta 2 and t-ACPD may selectively inhibit retinal glial mitogenesis mediated by activation of tyrosine kinase-linked receptors. Our experiments support the idea that endogenous antiproliferative molecules play a role in preventing glial proliferation in the retina.
Ikeda
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Department of Ophthalmology, University of Michigan, Ann Arbor, USA.
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D000470:Alkaloids; D053119:Benzophenanthridines; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009457:Neuroglia / Q000166:cytology*; D010617:Phenanthridines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012160:Retina / Q000166:cytology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000470:Alkaloids; D053119:Benzophenanthridines; D010617:Phenanthridines; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; D003515:Cycloleucine; D016222:Fibroblast Growth Factor 2; C036361:1-amino-1,3-dicarboxycyclopentane; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; C016299:chelerythrine; D011493:Protein Kinase C