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Proliferative responses of lymphoid cells to IL-2 and IL-4 depend on activation of the cells, but the mechanism(s) by which activation enhances cellular competence to respond to cytokines is not fully understood. The NF-kappaB/Rel family represents one signal transduction pathway induced during such activation. We show in this study that inhibition of NF-kappaB through the expression of an IkappaBalpha (inhibitory protein that dissociates from NF-kappaB) mutant refractory to signal-induced degradation (IkappaBalpha(DeltaN)) interfered with the acquisition of competence to proliferate in response to IL-4 as well as IL-2. Thymocytes and T cells from IkappaBalpha(DeltaN) transgenic mice expressed normal levels of IL-2R subunits. However, transgenic cells exhibited a dramatic defect in Stat5A activation treatment with IL-2, and a similar defect was observed for IL-4-induced Stat5. In contrast, T lymphoid cells with inhibition of NF-kappaB showed normal insulin receptor substrate-2 phosphorylation and only a modest decrease in Stat6 activation and insulin receptor substrate-1 phosphorylation after IL-4 stimulation. These results indicate that the NF-kappaB/Rel/IkappaBalpha system can regulate cytokine receptor capacitation through effects on the induction of downstream signaling by the Stat transcription factor family.