INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR-ALPHA SYNERGISTICALLY MEDIATENEUROTOXICITY - INVOLVEMENT OF NITRIC-OXIDE AND OF N-METHYL-D-ASPARTATE RECEPTORS

The cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha , produced by glial cells within the brain, appear to contribute to th e neuropathogenesis of several inflammatory neurodegenerative diseases ; however, little is known about the mechanism underlying cytokine-ind uced neurotoxicity. Using human fetal brain cell cultures composed of neurons and glial cells, we investigated the injurious effects of IL-1 beta and TNF-alpha, cytokines which are known to induce nitric oxide (NO) production by astrocytes. Although neither cytokine alone was tox ic, IL-1 beta and TNF-alpha in combination caused marked neuronal inju ry. Brain cell cultures treated with IL-1 beta plus TNF-alpha generate d substantial amounts of NO. Blockade of NO production with a NO synth ase inhibitor was accompanied by a marked reduction (about 45%) of neu ronal injury, suggesting that NO production by astrocytes plays a role in cytokine-induced neurotoxicity. Addition of N-methly-D-aspartate ( NMDA) receptor antagonists to brain cell cultures also blocked IL-1 be ta plus TNF-alpha-induced neurotoxicity (by 55%), implicating the invo lvement of NIMDA receptors in cytokine-induced neurotoxicity. Treatmen t of brain cell cultures with IL-1 beta plus TNF-alpha was found to in hibit [H-3]-glutamate uptake and astrocyte glutamine synthetase activi ty, two major pathways involved in NMDA receptor-related neurotoxicity . These in vitro findings suggest that agents which suppress NO produc tion or inhibit NMDA receptors may protect against neuronal damage in cytokine-induced neurodegenerative diseases. (C) 1995 Academic Press, Inc.