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Prepublished online as a Blood First Edition Paper on March 13, 2003; DOI 10.1182/blood-2002-08-2602. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-08-2602v1 102/1/207    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bream, J. H. Articles by Young, H. A. Search for Related Content PubMed PubMed Citation Articles by Bream, J. H. Articles by Young, H. A. Related Collections Immunobiology Signal Transduction Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 July 2003, Vol. 102, No. 1, pp. 207-214 IMMUNOBIOLOGY IL-4 synergistically enhances both IL-2– and IL-12–induced IFN- expression in murine NK cells Jay H. Bream, Rafael E. Curiel, Cheng-Rong Yu, Charles E. Egwuagu, Michael J. Grusby, Thomas M. Aune, and Howard A. Young From the Laboratory of Experimental Immunology, National Cancer Institute-Center for Cancer Research, Frederick, MD; Elanco Animal Health, a division of Eli Lilly, Greenfield, IN; Laboratory of Immunology, National Eye Institute, Bethesda, MD; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA; and Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN. Interleukin-4 (IL-4) is thought to influence T and natural killer (NK) cells by down-regulating T helper 1 (Th1)–type cytokines like interferon- (IFN-). While investigating IL-4 regulation of IFN- expression, we found that IL-4 synergized with IL-2 or IL-12 to enhance IFN- production and mRNA expression in spleen-derived, IL-2–cultured NK cells, as well as negatively sorted fresh DX5+/CD3- NK cells albeit at lower levels. The positive effect of IL-4 on IL-2–induced IFN- production was dependent upon signal transducer and activator of transcription 6 (Stat6) because this response was virtually abrogated in Stat6-/- mice. Notably, though, IL-12 plus IL-4 synergy on IFN- expression was intact in Stat6-/- mice. In exploring possible molecular mechanisms to account for the synergistic effects of IL-4 on murine NK cells, we found that IL-2 plus IL-4 stimulation resulted in a modest increase in tyrosine phosphorylation of Stat5, while IL-12 plus IL-4 treatment resulted in a more substantial increase in tyrosine-phosphorylated Stat4. Finally, to identify regions of the IFN- promoter that may be involved, NK cells from human IFN- promoter/luciferase transgenic mice were treated with cytokines. NK cells from proximal (-110 to +64) promoter region mice did not respond to cytokine stimulation; however, the intact -565 to +64 IFN- promoter responded synergistically to IL-2 plus IL-4 and to IL-12 plus IL-4 in NK cells. These data demonstrate a role for IL-4 in enhancing IFN- expression in murine NK cells that is partially dependent on Stat6 in IL-2 costimulation and completely independent of Stat6 in IL-12 costimulations. 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