A role for NF-κB activation in perforin expression of NK cells upon IL-2 receptor signaling

Optimal INK cell development and activation as well as cytolytic activity involves IL-2Rbeta signals that also up-regulate expression of the pore-forming effector molecule perforin. Although the Jak/Stat pathway and specifically Stat5 transcription factors are required to promote many of the respective downstream events, the role of additional signaling pathways and transcription factors remains to be clarified. This report investigates the role of NF-kappaB activation for perforin expression by NK cells. It is demonstrated that IL-2-induced up-regulation of perforin in primary NK cells and in a model cell line is blocked by two pharmacological agents known to inhibit NF-kappaB activation. Direct evidence for the activation of the NF-kappaB pathway by IL-2R signals in NK cells involves activation of the IKKalpha kinase, inhibitory protein kappaBalpha degradation, nuclear translocation of p50/p65 complexes, and ultimately, transcriptional activation of the perforin gene via an NF-kappaB binding element in its upstream enhancer. Taken together, these observations strongly suggest that IL-2R signals can activate a pathway leading to NF-kappaB activation in NK cells and that this pathway is involved in the control of perforin expression.