Inhibition of NF-AT-dependent transcription by NF-κB: Implications for differential gene expression in T helper cell subsets

Activation of individual CD4⁺ T cells results in differential lymphokine expression: interleukin 2 (IL-2) is preferentially produced by T helper type 1 (T(H)1) cells, which are involved in cell-mediated immune responses, whereas IL-4 is synthesized by T(H)2 cells, which are essential for humoral immunity. The Ca²⁺-dependent factor NF-AT(p) plays a key role in the inducible transcription of both these lymphokine genes. However, while IL2 expression requires the contribution of Ca²⁺- and protein kinase C- dependent signals, we report that activation of human IL4 transcription through the Ca²⁺-dependent pathway is diminished by protein kinase C stimulation in Jurkat T cells. This phenomenon is due to mutually exclusive binding of NF-AT(p) and NF-κB to the P sequence, an element located 69 bp upstream of the IL4 transcription initiation site. Human IL4 promoter- mediated transcription is downregulated in Jurkat cells stimulated with the NF-κB-activating cytokine tumor necrosis factor α and suppressed in RelA- overexpressing cells. In contrast, protein kinase C stimulation or RelA overexpression does not affect the activity of a human IL4 promoter containing a mouse P sequence, which is a higher-affinity site for NF-AT(p) and a lower-affinity site for RelA. Thus, competition between two general transcriptional activators, RelA and NF-AT(p), mediates the inhibitory effect of protein kinase C stimulation on IL4 expression and may contribute to differential gene expression in T(H) cells.