The cytokine contribution to the central nervous system (CNS) is currently being investigated, but conflicting results have frequently been found. Since, as stressed in the immune system, the cytokine action can be profoundly influenced by the synergistic and antagonistic interactions of the various cytokines present in the medium, a productive effect of the cytokine network in the repair processes and homeostasis recovery may also be dependent on their balanced response in the CNS. We, therefore, hypothesize that it is necessary to study the cytokine contribution to CNS events, evaluating cytokines both in their network and individually. Recent studies focus on interleukin 1 (IL-1) as a cytokine of primary importance for the outcome of diseases, and it seems to exert this role by regulating the synthesis of new proteins such as gamma interferon (IFN-gamma) cytokine which has been reported as having a very important early role in the balance of interactions in the cytokine network. On this basis, to verify the above hypothesis, we determined the release level of IL-1beta and IFN-gamma cytokines in media of cultured rat hippocampal neurons under physiological and anoxic conditions with and without 2-amino-5-phosphonopentanoate (AP5; an N-methyl-D-aspartate receptor antagonist). Our results show that these cytokines are released in these media, and the anoxic insult seems to determine an increase in IL-1beta and a decrease in IFN-gamma release levels as compared to those under the physiological condition. Moreover, while the IL-1beta and IFN-gamma releases covary positively in the physiological media (because an increase in the IL1-beta level is paralleled by an increase in IFN-gamma), the anoxic insult renders this interaction negative (as the IL-1beta level increase corresponds to a decrease in the IFN-gamma level). These data led us to suggest that IFN-gamma may have a physiological regulating role in the IL-1 neurotoxic action and homeostasis recovery following an insult. In fact, the addition of AP5 before anoxic exposure resulted in a significant increase of cellular survival, but also in a decrease of IL-1beta release and a re-establishment of IL-1beta and IFN-gamma release relations to the initial condition without stress. Our overall results, therefore, sustain our hypothesis on the importance of studying the role of cytokines both in their network and individually.