TY - JOUR
T1 - Interleukin-1 and tumor necrosis factor-α synergistically mediate neurotoxicity
T2 - Involvement of nitric oxide and of n-methyl-d-aspartate receptors
AU - Chao, Chun C.
AU - Hu, Shuxian X.
AU - Ehrlich, Laura
AU - Peterson, Phillip K.
PY - 1995/12
Y1 - 1995/12
N2 - 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.
AB - 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.
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U2 - 10.1006/brbi.1995.1033
DO - 10.1006/brbi.1995.1033
M3 - Article
C2 - 8903852
AN - SCOPUS:0029620390
SN - 0889-1591
VL - 9
SP - 355
EP - 365
JO - Brain Behavior and Immunity
JF - Brain Behavior and Immunity
IS - 4
ER -