Regulation of Nuclear Gamma Interferon Gene Expression by Interleukin 12 (IL-12) and IL-2 Represents a Novel Form of Posttranscriptional Control

Posttranscriptional control of gamma interferon (IFN-γ) gene expression has not been extensively studied and is poorly understood. Our work describes a posttranscriptional mechanism that modulates IFN-γ mRNA expression in stimulated natural killer (NK) cells through nuclear retention of the IFN-γ mRNA. This is evidenced by the elevated and sustained nuclear accumulation of both precursor and processed IFN-γ mRNAs in NK cells stimulated with interleukin-12 (IL-12). The elevated nuclear mRNA accumulation persists long after transcriptional activity has subsided and the rate of cytoplasmic IFN-γ mRNA accumulation has dropped. The IL-12-induced nuclear retention of the IFN-γ mRNA prevails until a secondary cytokine stimulus is received. The secondary stimulus, which is initiated by IL-2, mediates transcription-independent movement of the nuclear IFN-γ mRNA. Concurrent with the nucleocytoplasmic movement of the IFN-γ mRNA, we have observed increases in the amount of processed nuclear IFN-γ mRNA that are greater than that seen for the unprocessed IFN-γ mRNA. The increase in processed IFN-γ mRNA appears to be due to increased mRNA stability which then promotes increased nucleocytoplasmic shuttling of the mature IFN-γ mRNA. These data support a model whereby mobilization of nuclear IFN-γ mRNA stores allows NK cells to rapidly and robustly respond to secondary cytokine activators in a transcription-independent manner, thus shortening the time for overall cellular response to inflammatory signals.