Rel/NF-kappaB transcription factors are involved in several physiological processes, including the regulation of apoptosis. These factors were shown to exhibit pro- or anti-apoptotic activities in different cellular models, but at present, the mechanisms underlying these opposite effects are poorly understood. In this study, we show that the constitutive expression of a transcriptionally active member of the Rel/NF-kappaB family, c-Rel, first induces a resistance against TNFalpha-induced apoptosis and later increases the level of spontaneous apoptosis of HeLa cells. Both the anti- and pro-apoptotic effects increase with the level of c-Rel overexpression. The up-regulation by c-Rel of the manganese superoxide dismutase (MnSOD) could explain both the rapid anti-apoptotic effect and the delayed pro-apoptotic one. Indeed, the enzymatic activity of MnSOD is to transform the toxic O(2)(*)(-) in H(2)O(2). Hence, on one hand, its induction helps cells to resist against the apoptogenic burst of O(2)(*)(-) produced upon TNFalpha stimulation, but on the other hand, it leads to a progressive H(2)O(2) accumulation that ultimately results in apoptosis. These results indicate that the anti- and pro-apoptotic effects of Rel/NF-kappaB factors are not necessarily alternative but can occur successively in the same cell, via the up-regulation of the same target gene.