Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways

The proinflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha ar e produced within the CNS, and, similar to the periphery, they have pleotro phic and overlapping functions. We have shown previously that TNF-alpha inc reases neuronal survival to a toxic influx of calcium mediated through neur onal N-methyl-D-aspartic acid (NMDA) glutamate-gated ion channels. This pro cess, termed excitotoxicity, is a major contributor to neuronal death follo wing ischemia or stroke. Neuroprotection by this cytokine requires both act ivation of the p55/TNF receptor type I and the release of TNF-alpha from ne urons, 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 als o neuroprotective to excessive NMDA challenge in our system. Neuroprotectio n 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 inhibi ted 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 re ceptor antagonist and it is not affected by nicotine. However, neutralizing anti-NGF only partially blocks IL-6-mediated protection. These studies sup port an important role for distinct but overlapping neuroprotective cytokin e effects in the CNS.