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

Abstract

Posttranscriptional control of gamma interferon (IFN-␥) gene expression has not been extensively studied and is poorly understood. Our work describes a posttranscriptional mechanism that modulates IFN-␥ mRNA expression in stimulated natural killer (NK) cells through nuclear retention of the IFN-␥ mRNA. This is evidenced by the elevated and sustained nuclear accumulation of both precursor and processed IFN-␥ 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-␥ mRNA accumulation has dropped. The IL-12-induced nuclear retention of the IFN-␥ 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-␥ mRNA. Concurrent with the nucleocytoplasmic movement of the IFN-␥ mRNA, we have observed increases in the amount of processed nuclear IFN-␥ mRNA that are greater than that seen for the unprocessed IFN-␥ mRNA. The increase in processed IFN-␥ mRNA appears to be due to increased mRNA stability which then promotes increased nucleocytoplasmic shuttling of the mature IFN-␥ mRNA. These data support a model whereby mobilization of nuclear IFN-␥ 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.

Aryl Hydrocarbon Receptor Activation during Influenza Virus Infection Unveils a Novel Pathway of IFN-γ Production by Phagocytic Cells

“…For instance, many studies have demonstrated that IFN-␥ production by lymphocytes is stimulated by IL-12, IL-18, IFN␣␤, and IL-2 (15)(16)(17)(18). We have previously shown that AhR activation by TCDD suppresses pulmonary IL-12 levels (22, 24) and does not alter IFN-␣␤, TNF, IL-1, or IL-18 levels in the lung during infection (25).…”

“…However, several additional cellular sources of IFN-␥ have been reported, including ␥ѨT cells, NKT cells, macrophages, dendritic cells, neutrophils, and B cells (6 -14). The production of IFN-␥ by T cells and NK cells is regulated by many cytokines, in particular IL-2, IL-12, IL-18, and IFN-␣␤ (15)(16)(17)(18). In addition to cytokines, IFN-␥ expression in T cells is controlled by multiple transcriptional regulators, including NF-B, NFAT, and ATF2 (19 -21).…”

Comparison of mammary gland involution between 129S1 and C57BL/6 inbred mouse strains: differential regulation of Bcl2a1, Trp53, Cebpb, and Cebpd expression

“…The peak of Trp53 expression on day 1 coincides with the downregulation of Bcl2a1 in Figure 3 Comparison of Bcl2 family gene expression in involuting mammary glands of 129S1 and C57BL/6 mice. RNA was isolated from abdominal mammary gland tissue at the indicated time points of involution and subjected to multiprobe ribonuclease protection assays as described (Hodge et al, 2002), using the mAPO-2 multiprobe template set (PharMingen). Data shown are the phosphoimage quantifications of the indicated genes' expression levels in two mice per strain normalized to L32 expression (arbitrary units).…”

Post-transcriptional control of the interferon system

“…In almost all cases, this increased stability was shown to be dependent upon p38 mitogen activated protein kinase (p38 MAPK) activity, as the stability was not observed when inhibitors of this pathway were included in the assay. These various stimulations include: treatment of T and NK cells with IL-2 + IL-12 [28][29][30][31][32]; IL-12 + IL-18 treatment of NK cells [32]; anti-CD3 + anti-CD28 or anti-CD2 treatment of T cells [33] with a similar study comparing cells obtained from old and young mice [34]; CD4+ memory T cells activated by OX40L [35]; treatment of both CD4+ and CD8+ T cells with IL-2 and bryostatin [36]; and stimulation of Jurkat T cells with anti-LFA1 and anti-CD3 [37]. In addition, our laboratory (H.A.Y.)…”