Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: 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 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.
Neuroimmunobiology and Host Defense Laboratory, Minneapolis Medical Research Foundation, Minnesota 55404, USA.
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CC
Chao
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Hu
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Ehrlich
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Peterson
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D015415:Biomarkers; D016923:Cell Death; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005974:Glutamate-Ammonia Ligase / Q000096:biosynthesis / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007249:Inflammation; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology*; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008954:Models, Biological; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D015415:Biomarkers; D018691:Excitatory Amino Acid Antagonists; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D005974:Glutamate-Ammonia Ligase