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Molecular and Cellular Biology, March 2002, p. 1742-1753, Vol. 22, No. 6
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.6.1742-1753.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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

Deborah L. Hodge,1 Alfredo Martinez,2 John G. Julias,3 Lynn S. Taylor,1 and Howard A. Young1*

Laboratory of Experimental Immunology,1 HIV Drug Resistance Program, National Cancer Institute-Center for Cancer Research, FrederickMaryland 21702,,3 Department of Cell and Cancer Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208922

Received 22 June 2001/ Returned for modification 31 August 2001/ Accepted 30 November 2001

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

* Corresponding author. Mailing address: Laboratory of Experimental Immunology, National Cancer Institute-Center for Cancer Research, Frederick, MD 21702-1201. Phone: (301) 846-5700. Fax: (301) 846-1673. E-mail: youngh{at}mail.ncifcrf.gov.

Molecular and Cellular Biology, March 2002, p. 1742-1753, Vol. 22, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.6.1742-1753.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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