CYTOKINE MODULATION OF MURINE MICROGLIAL CELL SUPEROXIDE PRODUCTION

Activated microglia may contribute to two opposite effects during infl ammation within the central nervous system: host defense against micro organisms and neuronal injury. Each of these processes may be mediated by the generation of reactive oxygen intermediates by activated micro glia. We investigated the effects of two proinflammatory cytokines, in terferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, and of the anti-inflammatory cytokine, transforming growth factor (TGF)-beta, on murine microglial cell superoxide (O-2(-)) production upon stimulatio n with phorbol myristate acetate (PMA). Priming of microglia with IFN- gamma or TNF-alpha resulted in a dose-dependent enhancement of O-2(-) release in response to PMA. The priming effects of these two cytokines were additive, suggesting that they acted by independent mechanisms. We also found that IFN-gamma and TNF-alpha stimulated the release of b ioactive TGF-beta and that treatment of microglial cell cultures with TGF-beta antagonized the priming effects of IFN-gamma and TNF-alpha on O-2(-) production. The results of this study have implications for un derstanding the mechanisms by which cytokines and microglia may contri bute to host defense as well as to injury of the brain. (C) 1995 Wiley -Liss, Inc.