Abstract To investigate the physiological significance of microglia-derived plasminogen (PGn) in the central nervous system, we determined the effects of rat PGn on the secretion of plasminogen activator inhibitor (PAI) in cultured rat astrocytes by reverse zymography and Western blotting. The cultured astrocytes normally produce only a limited amount of PAI-1. After stimulation with PGn, however, the amount of active PAI-1 in the astrocyte-conditioned medium was significantly increased in a time-dependent manner. PGn was also proved to activate p38 MAP kinase and c-Jun N-terminal kinase in these astrocytes. Taken together, these results suggest that microglia-derived PGn increases the secretion of PAI-1 in astrocytes through the activation of MAP kinases, and that enhanced PAI-1 regulates various physiological phenomena including tissue remodeling, neuronal plasticity and neurotoxicity.