Abstract
The cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, 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-1beta and TNF-alpha, cytokines which are known to induce nitric oxide (NO) production by astrocytes. Although neither cytokine alone was toxic, IL-1beta and TNF-alpha in combination caused marked neuronal injury. Brain cell cultures treated with IL-1beta plus TNF-alpha 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-1beta plus TNF-alpha-induced neurotoxicity (by 55%), implicating the involvement of NMDA receptors in cytokine-induced neurotoxicity. Treatment of brain cell cultures with IL-1beta plus TNF-alpha 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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
2-Amino-5-phosphonovalerate / pharmacology
-
Astrocytes / drug effects
-
Astrocytes / metabolism
-
Biological Transport / drug effects
-
Biomarkers
-
Cell Death
-
Cells, Cultured
-
Dizocilpine Maleate / pharmacology
-
Drug Synergism
-
Enzyme Induction / drug effects
-
Excitatory Amino Acid Antagonists / pharmacology
-
Glutamate-Ammonia Ligase / biosynthesis
-
Glutamate-Ammonia Ligase / genetics
-
Glutamic Acid / metabolism
-
Glutamic Acid / pharmacology
-
Humans
-
Inflammation
-
Interleukin 1 Receptor Antagonist Protein
-
Interleukin-1 / pharmacology
-
Interleukin-1 / physiology*
-
L-Lactate Dehydrogenase / analysis
-
Models, Biological
-
N-Methylaspartate / antagonists & inhibitors
-
Nerve Tissue Proteins / biosynthesis
-
Nerve Tissue Proteins / genetics
-
Neuroglia / drug effects*
-
Neuroglia / metabolism
-
Neurons / drug effects*
-
Nitric Oxide / biosynthesis
-
Nitric Oxide / physiology*
-
Nitric Oxide Synthase / biosynthesis
-
Nitric Oxide Synthase / genetics
-
Receptors, N-Methyl-D-Aspartate / drug effects
-
Receptors, N-Methyl-D-Aspartate / physiology*
-
Recombinant Proteins / pharmacology
-
Sialoglycoproteins / pharmacology
-
Tumor Necrosis Factor-alpha / pharmacology
-
Tumor Necrosis Factor-alpha / physiology*
-
omega-N-Methylarginine / pharmacology
Substances
-
Biomarkers
-
Excitatory Amino Acid Antagonists
-
IL1RN protein, human
-
Interleukin 1 Receptor Antagonist Protein
-
Interleukin-1
-
Nerve Tissue Proteins
-
Receptors, N-Methyl-D-Aspartate
-
Recombinant Proteins
-
Sialoglycoproteins
-
Tumor Necrosis Factor-alpha
-
omega-N-Methylarginine
-
Nitric Oxide
-
Glutamic Acid
-
N-Methylaspartate
-
Dizocilpine Maleate
-
2-Amino-5-phosphonovalerate
-
L-Lactate Dehydrogenase
-
Nitric Oxide Synthase
-
Glutamate-Ammonia Ligase