Alcohol blocks TNF alpha but not other cytokine-mediated neuroprotection to NMDA

Background: We have investigated the effects of ethanol/alcohol (ETOH) on t he pro-inflammatory CNS cytokine network that mediates neuroprotection to a n excitotoxic challenge with the glutamate receptor agonist N-methyl-D-aspa rtic acid (NMDA). Methods: Cultured murine cortical neurons were incubated with either TNF al pha, IL-1 alpha, IL-I beta, or IL-6 in the presence or absence of 20 mM ETC H, maintained in an alcohol equilibrated humidified chamber, and the effect s of these cytokines on neuronal survival after a chronic 20 hr exposure to NMDA was quantified. Results: Neuroprotection induced by TNF alpha, but not IL-1 alpha, IL-1 bet a, or IL-6, was inhibited by a concentration of alcohol (20 mM) that alone did not neuroprotect. Alcohol also affected the paracrine/autocrine inducti on of cytokine transcripts in neuronal cell cultures, which included enhanc ing the ability of TNF alpha to stimulate IL-6 transcripts. This result sup ports distinct cytokine-modulated neuroprotective pathways of which only TN F alpha is sensitive to low alcohol concentrations. We have shown previousl y that nicotine, acting through an alpha-bungarotoxin sensitive receptor, i s also neuroprotective, but it too specifically abolishes TNF alpha-mediate d neuroprotection. However, alcohol did not affect nicotine-induced neuropr otection. Conclusions: We suggest that the effects of low concentrations of alcohol o n neuronal cytokine networks proceed through antagonism of neuroprotective pathway(s) unique to TNF alpha.