title: Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways.
abstract: The proinflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha are produced within the CNS, and, similar to the periphery, they have pleotrophic and overlapping functions. We have shown previously that TNF-alpha increases neuronal survival to a toxic influx of calcium mediated through neuronal N-methyl-d -aspartic acid (NMDA) glutamate-gated ion channels. This process, termed excitotoxicity, is a major contributor to neuronal death following ischemia or stroke. Neuroprotection by this cytokine requires both activation of the p55/TNF receptor type I and the release of TNF-alpha from neurons, and it is inhibited by the plant alkaloid nicotine. Here, we report that other inflammatory cytokines (IL-1 alpha, IL-1 beta, and IL-6) are also neuroprotective to excessive NMDA challenge in our system. Neuroprotection provided by IL-1 is distinct from TNF-alpha because it is inhibited by IL-1 receptor antagonist; it is not antagonized by nicotine, but it is inhibited by a neutralizing Ab to nerve growth factor (NGF). Similar to IL-1, IL-6-mediated neuroprotection is also antagonized by pretreatment with IL-1 receptor antagonist and it is not affected by nicotine. However, neutralizing anti-NGF only partially blocks IL-6-mediated protection. These studies support an important role for distinct but overlapping neuroprotective cytokine effects in the CNS.
authors.affiliation: Geriatric Research Education and Clinical Center, Veterans Administration Medical Center, Salt Lake City, UT 84112, USA.
authors.forename: N G
authors.initials: NG
authors.lastname: Carlson
authors.forename: W A
authors.initials: WA
authors.lastname: Wieggel
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: A
authors.initials: A
authors.lastname: Bacchi
authors.forename: S W
authors.initials: SW
authors.lastname: Rogers
authors.forename: L C
authors.initials: LC
authors.lastname: Gahring
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex; D007106:Immune Sera / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity; D009414:Nerve Growth Factors / Q000276:immunology / Q000502:physiology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000276:immunology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D012795:Sialoglycoproteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: C507764:Il1rn protein, mouse; D007106:Immune Sera; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D009414:Nerve Growth Factors; D009498:Neurotoxins; D018733:Nicotinic Antagonists; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D016202:N-Methylaspartate; D009538:Nicotine