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Blood, 15 April 2008, Vol. 111, No. 8, pp. 4173-4183. Prepublished online as a Blood First Edition Paper on January 3, 2008; DOI 10.1182/blood-2007-01-068908. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-01-068908v1 111/8/4173    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 CrossRef Google Scholar Articles by Kondadasula, S. V. Articles by Carson, W. E. PubMed PubMed Citation Articles by Kondadasula, S. V. Articles by Carson, W. E., III Related Collections Chemokines, Cytokines, and Interleukins Immunobiology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Colocalization of the IL-12 receptor and FcRIIIa to natural killer cell lipid rafts leads to activation of ERK and enhanced production of interferon- Sri Vidya Kondadasula*,1, Julie M. Roda*,2, Robin Parihar1, Jianhua Yu1,3, Amy Lehman4, Michael A. Caligiuri1,3, Susheela Tridandapani3, Richard W. Burry5, and William E. Carson, III1,2,6 1 Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics program, 2 Integrated Biomedical Sciences Graduate Program, 3 Department of Internal Medicine, 4 Center for Biostatistics, 5 Department of Neuroscience, and 6 Department of Surgery, The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus Natural killer (NK) cells express an activating receptor for the Fc portion of IgG (FcRIIIa) that mediates interferon (IFN)– production in response to antibody (Ab)–coated targets. We have previously demonstrated that NK cells activated with interleukin-12 (IL-12) in the presence of immobilized IgG secrete 10-fold or more higher levels of IFN- as compared with stimulation with either agent alone. We examined the intracellular signaling pathways responsible for this synergistic IFN- production. NK cells costimulated via the FcR and the IL-12 receptor (IL-12R) exhibited enhanced levels of activated STAT4 and Syk as compared with NK cells stimulated through either receptor alone. Extracellular signal–regulated kinase (ERK) was also synergistically activated under these conditions. Studies with specific chemical inhibitors revealed that the activation of ERK was dependent on the activation of PI3-K, whose activation was dependent on Syk, and that sequential activation of these molecules was required for NK cell IFN- production in response to FcR and IL-12 stimulation. Retroviral transfection of ERK1 into primary human NK cells substantially increased IFN- production in response to immobilized IgG and IL-12, while transfection of human NK cells with a dominant-negative ERK1 abrogated IFN- production. Confocal microscopy and cellular fractionation experiments revealed that FcRIIIa and the IL-12R colocalized to areas of lipid raft microdomains in response to costimulation with IgG and IL-12. Chemical disruption of lipid rafts inhibited ERK signaling in response to costimulation and significantly inhibited IFN- production. These data suggest that dual recruitment of FcRIIIa and the IL-12R to lipid raft microdomains allows for enhanced activation of downstream signaling events that lead to IFN- production. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Rafting with the IL-12 receptor Daniel W. McVicar Blood 2008 111: 3911-3912. [Full Text] [PDF]

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