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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 (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 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 Citing Articles via Google Scholar Google Scholar Articles by Kondadasula, S. V. Articles by Carson, W. E. Search for Related Content PubMed PubMed Citation Articles by Kondadasula, S. V. Articles by Carson, W. E. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 19, 2007 Accepted December 5, 2007 Co-localization 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, Julie M Roda, Robin Parihar, Jianhua Yu, Amy Lehman, Michael A. Caligiuri, Susheela Tridandapani, Richard W Burry, and William E. Carson* Human Cancer Genetics program, Department of Molecular Virology, Immunology and Medical Genetics, The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State Univ., Columbus, OH, United States Integrated Biomedical Sciences Graduate Program, The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State Univ., Columbus, OH, United States Center for Biostatistics, The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State Univ., Columbus, OH, United States Department of Internal Medicine, The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State Univ., Columbus, OH, United States Department of Neuroscience, The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State Univ., Columbus, OH, United States Department of Surgery, The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State Univ., Columbus, United States * Corresponding author; email: william.carson{at}osumc.edu. Natural killer (NK) cells express an activating receptor for the Fc portion of IgG (FcRIIIa) that mediates interferon (IFN)- production in response to Ab-coated targets. We have previously demonstrated that NK cells activated with interleukin (IL)-12 in the presence of immobilized IgG secrete >10 fold higher levels of IFN- as compared to stimulation with either agent alone. We have now examined the intracellular signaling pathways responsible for this synergistic IFN- production. NK cells co-stimulated via the FcR and the IL-12 receptor (IL-12R) exhibited enhanced levels of activated STAT4 and Syk as compared to NK cells stimulated through either receptor alone. 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, in turn, 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 co-localized to areas of lipid raft micro-domains in response to co-stimulation with IgG and IL-12. Chemical disruption of lipid rafts inhibited ERK signaling in response to co-stimulation and significantly inhibited IFN- production. Taken together, these data suggest that dual recruitment of FcRIIIa and the IL-12R to lipid raft micro-domains 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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