Interleukin-1 and tumor necrosis factor-α synergistically mediate neurotoxicity: Involvement of nitric oxide and of n-methyl-d-aspartate receptors

Chun C. Chao, Shuxian X. Hu, Laura Ehrlich, Phillip K. Peterson

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345 Scopus citations

Abstract

The cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-α, produced by glial cells within the brain, appear to contribute to the neuropathogenesis of several inflammatory neurodegenerative diseases; however, little is known about the mechanism underlying cytokine-induced neurotoxicity. Using human fetal brain cell cultures composed of neurons and glial cells, we investigated the injurious effects of IL-1 β and TNF-α, cytokines which are known to induce nitric oxide (NO) production by astrocytes. Although neither cytokine alone was toxic, IL-1 β and TNF-α in combination caused marked neuronal injury. Brain cell cultures treated with IL-1 β plus TNF-α generated substantial amounts of NO. Blockade of NO production with a NO synthase inhibitor was accompanied by a marked reduction (about 45%) of neuronal 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 β plus TNF-α-induced neurotoxicity (by 55%), implicating the involvement of NIMDA receptors in cytokine-induced neurotoxicity. Treatment of brain cell cultures with IL-1 β plus TNF-α was found to inhibit [3H]-glutamate uptake and astrocyte glutamine synthetase activity, two major pathways involved in NMDA receptor-related neurotoxicity. These in vitro findings suggest that agents which suppress NO production or inhibit NMDA receptors may protect against neuronal damage in cytokine-induced neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)355-365
Number of pages11
JournalBrain Behavior and Immunity
Volume9
Issue number4
DOIs
StatePublished - Dec 1995

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Copyright 2017 Elsevier B.V., All rights reserved.

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