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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 (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 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 Social Bookmarking                   What's this? Submitted August 26, 2002 Accepted February 27, 2003 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 Laboratory of Experimental Immunology, National Cancer Institute, Frederick, MD, USA Elanco Animal Health, Eil Lilly and Company, Greenville, IN, USA Laboratory of Immunology, National Eye Institute, Bethesda, MD, USA Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA * Corresponding author; email: breamj{at}mail.nih.gov. IL-4 is thought to influence T and NK cells by down-regulating Th1 type cytokines, including 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. While NK cells from C57Bl/6 Stat6-/- mice displayed an almost 10-fold drop in IFN- production in response to IL-4 and IL-2, IL-12/IL-4 synergy 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/IL-4 stimulation resulted in a modest increase in tyrosine phosphorylation of Stat5, while IL-12/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 cytokines, however, the intact -565 to +64 IFN- promoter responded synergistically to IL-2/IL-4 in NK cells. These data suggest a role for IL-4 in enhancing IFN- expression in murine NK cells that is partially dependent on Stat6 in IL-2 co-stimulation, and completely independent of Stat6 in IL-12 co-stimulations. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. Becknell, T. L. Hughes, A. G. Freud, B. W. Blaser, J. Yu, R. Trotta, H. C. Mao, M. L. Caligiuri de Jesus, M. Alghothani, D. M. Benson Jr, et al. Hlx homeobox transcription factor negatively regulates interferon-{gamma} production in monokine-activated natural killer cells Blood, March 15, 2007; 109(6): 2481 - 2487. [Abstract] [Full Text] [PDF] S. C. Morris, T. Orekhova, M. J. Meadows, S. M. Heidorn, J. Yang, and F. D. Finkelman IL-4 Induces In Vivo Production of IFN-{gamma} by NK and NKT Cells J. Immunol., May 1, 2006; 176(9): 5299 - 5305. [Abstract] [Full Text] [PDF] A. Suto, H. Nakajima, N. Tokumasa, H. Takatori, S.-i. Kagami, K. Suzuki, and I. Iwamoto Murine Plasmacytoid Dendritic Cells Produce IFN-{gamma} upon IL-4 Stimulation J. Immunol., November 1, 2005; 175(9): 5681 - 5689. [Abstract] [Full Text] [PDF] C. H. Yun, A. Lundgren, J. Azem, A. Sjoling, J. Holmgren, A.-M. Svennerholm, and B. S. Lundin Natural Killer Cells and Helicobacter pylori Infection: Bacterial Antigens and Interleukin-12 Act Synergistically To Induce Gamma Interferon Production Infect. Immun., March 1, 2005; 73(3): 1482 - 1490. [Abstract] [Full Text] [PDF] V. G. Pillarisetty, S. C. Katz, J. I. Bleier, A. B. Shah, and R. P. DeMatteo Natural Killer Dendritic Cells Have Both Antigen Presenting and Lytic Function and in Response to CpG Produce IFN-{gamma} via Autocrine IL-12 J. Immunol., March 1, 2005; 174(5): 2612 - 2618. [Abstract] [Full Text] [PDF] J. H. Bream, D. L. Hodge, R. Gonsky, R. Spolski, W. J. Leonard, S. Krebs, S. Targan, A. Morinobu, J. J. O'Shea, and H. A. Young A Distal Region in the Interferon-{gamma} Gene Is a Site of Epigenetic Remodeling and Transcriptional Regulation by Interleukin-2 J. Biol. Chem., September 24, 2004; 279(39): 41249 - 41257. [Abstract] [Full Text] [PDF]

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