Hydrogen peroxide induces the death of astrocytes through the down-regulation of the constitutive nuclear factor-kappaB activity.

Nuclear factor-kappaB (NF-kappaB) has a dual role in the promotion or attenuation of cell death. Here, we demonstrated the role of NF-kappaB in the H(2)O(2)-induced death of astrocytes. H(2)O(2) evoked the release of lactate dehydrogenase (LDH), a marker of cell death, and concomitantly decreased the DNA binding and transcriptional activity of NF-kappaB in cultured astrocytes. H(2)O(2)-induced astrocyte death was markedly increased by the co-treatment with pyrrolidinedithiocarbamate, an NF-kappaB inhibitor. Moreover, the elevation of constitutive NF-kappaB activity by overexpressing p65 NF-kappaB subunit attenuated H(2)O(2) toxicity, whereas NF-kappaB inhibition by overexpressing IkappaB potentiated the toxicity. NF-kappaB activity and H(2)O(2) cytotoxicity was further found to be dependent on cell density. Compared with astrocytes in low cell density, those in high cell density exhibited a higher constitutive NF-kappaB activity and a stronger resistance to H(2)O(2) cytotoxicity. These results indicate that the constitutive activity of NF-kappaB in astrocytes is required for their survival under oxidative stress such as H(2)O(2).