DIFFERENTIAL REGULATION OF ASTROCYTE PLASMINOGEN ACTIVATORS BY INSULIN-LIKE GROWTH-FACTOR-I AND EPIDERMAL GROWTH-FACTOR

Rat astrocytes synthesize and secrete two types of plasminogen activat ors (PAs), tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), whose functions are related to cell pro liferation, migration, and differentiation during development. The reg ulation of PAs produced by brain astrocytes is poorly understood. In a previous report we demonstrated that t-PA and u-PA are each independe ntly regulated by cAMP-dependent protein kinase and protein kinase-C. In the present study we examined the effects of three well characteriz ed astrocyte mitogens, insulin-like growth factor-I (IGF-I), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF), on th e PA activities produced and secreted by rat astrocytes in vitro. We f ound that IGF-I and EGF increase cell-associated total PA activity in astrocyte-conditioned medium (CM). The effects of both growth factors were dose and time dependent, and maximal stimulation was achieved aft er 72 h of treatment with the highest dose tested (100 nM). IGF-I stim ulated the cell-associated PA activity more than the CM activity, wher eas EGF showed an opposite pattern, suggesting that the secretion of P A is differentially modulated by IGF-I and EGF. PDGF had no effect on astrocyte PA activities at any dose or time point included in the stud y. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis/zymograph y showed type-specific changes in CM and cell-associated PA activity a fter growth factor treatment. IGF-I stimulated only t-PA, whereas EGF induced a marked increase in u-PA activity and a more limited increase in t-PA. PDGF did not modify either t-PA or u-PA activity. In summary , our results show that IGF-I and E6F each had different effects on PA activities, whereas PDGF had no effect. This diversity in the pattern s of growth factor regulation of PAs suggests that the production of a strocyte PAs is not simply related to mitogenesis. More likely, astroc yte PAs are involved in a wide range of growth factor-mediated actions in the developing brain.