Carlson NG, Wieggel WA, Chen J, Bacchi A, Rogers SW, Gahring LC. Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways, J Immunol 163(7) :3963-8, 1999.

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 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. Important points: -model: mouse culture (embryological 14-16) -IL-1 a or B, IL-6 or TNF-a did not cause neuron death -all increase neuron survival after challenge by NMDA -TNF-a protection is concentration dependent, and non-linear (100 ng/ml increases survival by @ 15%; 200ng/ml only @ 5%) -TNF-a effects blocked by TNF-a antagonist; IL-1a and B and IL-6 blocked by IL-1 receptor antagonist (ra) -anti-NGF Ab inhibits IL-1 protection, IL-6 (partially) but not TNF-a protection -cytokines also modulate neurotransmitter receptor function: IL-1 increases GABA receptor-mediated inhibition; TNF-a decreases excitotoxicity by modulating the NMDA receptor -opposite effects on neuronal survival are observed for IL-1 in vivo (toxic) vs. in vitro (protective) -concentration is probably key: low IL-1 concentration may be protective whereas high is toxic

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