The tumor promoting compound 12-O-tetradecanoyl-phorbol-13-acetate (TPA) specifically binds to and activates protein kinase C (PKC). This enzyme is widely distributed in the brain. It plays a pivotal role in transmembrane signalling. Arachidonic acid conversion is a common cellular response to membrane perturbation. We report that TPA evokes synthesis and release of the cyclo-oxygenation product prostaglandin E by cultured rat astrocytes. The inert stereo-isomer 4 alpha-phorbol 12,13-didecanoate, was devoid of stimulatory activity. We conclude that activation of PKC is a crucial step in the initiation of the arachidonic acid cascade in astrocytes. It is suggested that production of proinflammatory and immunomodulating mediators derived from arachidonate by astrocytes may be relevant in the context of normal and aberrant immune responses within the central nervous system.