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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1468-1475. Prepublished online as a Blood First Edition Paper on October 25, 2005; DOI 10.1182/blood-2005-04-1579. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: 2005-04-1579v1 107/4/1468    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 Ortaldo, J. R Articles by Young, H. A Search for Related Content PubMed PubMed Citation Articles by Ortaldo, J. R Articles by Young, H. A Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 21, 2005 Accepted October 2, 2005 Regulation of ITAM positive receptors: role of IL-12 and IL-18 John R Ortaldo, Robin Winkler-Pickett, Jon Wigginton, Meagan Horner, Earl W Bere, Anna T Mason, Narayan Bhat, James Cherry, Michael Sanford, Deborah L Hodge, and Howard A Young* Laboratory of Experimental Immunology, National Cancer Institute-Center for Cancer Research, Frederick, MD, USA Pediatric Oncology Branch, National Cancer Institute-Center for Cancer Research, Bethesda, MD, USA Basic Research Program, SAIC Frederick, Frederick, MD, USA * Corresponding author; email: youngh{at}ncifcrf.gov. Our previous studies have identified mechanisms by which cytokine production, blocked by Ly49G2 receptor crosslinking, can be overridden. In this manuscript, we have analyzed the regulation of other ITAM positive receptor signaling on NK, NKT and T cells and characterized the biochemical pathways involved in this signaling. Our studies demonstrate that crosslinking of NKG2D and NK1.1 results in a synergistic NK IFN-; response when combined with IL-12 or IL-18. Examination of NKT and T cell responses demonstrated that cross-linking of NKG2D and CD3 resulted in potent synergy when combined with IL-12, and to a lesser degree with IL-18. We have now found that both the p38 MAP kinase and the ERK dependent signal transduction pathways are required for the synergistic response. Further mechanistic examination of the synergy indicated a potent upregulation of total IFN-; mRNA in both the nuclear and cytoplasmic compartment but mRNA halflife was not affected. Fifteen minutes of IL-12 pretreatment was sufficient to result in maximal synergistic activation indicating that the response of the cells to the IL-12 signal is rapid and immediate. Thus our data demonstrates that multiple convergent signals maximize the innate immune response by triggering complimentary biochemical signaling pathways. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. A. Haddad, L. K. Senger, and F. Takei An Accessory Role for B Cells in the IL-12-Induced Activation of Resting Mouse NK Cells J. Immunol., September 15, 2009; 183(6): 3608 - 3615. [Abstract] [Full Text] [PDF] H.-T. LEE, W.-S. CHEN, K.-H. SUN, C.-T. CHOU, and C.-Y. TSAI Increased Spontaneous But Decreased Mitogen-stimulated Expression and Excretion of Interleukin 18 by Mononuclear Cells in Patients with Active Systemic Lupus Erythematosus J Rheumatol, September 1, 2009; 36(9): 1910 - 1916. [Abstract] [Full Text] [PDF] I. 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