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Blood, 1 March 2007, Vol. 109, No. 5, pp. 2234-2242. Prepublished online as a Blood First Edition Paper on November 2, 2006; DOI 10.1182/blood-2006-07-037473. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2006-07-037473v1 109/5/2234    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 Rafei, M. Articles by Galipeau, J. Search for Related Content PubMed PubMed Citation Articles by Rafei, M. Articles by Galipeau, J. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 25, 2006 Accepted October 17, 2006 A GMCSF & IL15 fusokine leads to paradoxical immunosuppression in vivo via asymmetrical JAK/STAT signalling through the IL15 receptor complex Moutih Rafei, Jian Hui Wu, Borhane Annabi, Laurence Lejeune, Moira Francois, and Jacques Galipeau* Montreal Centre for Experimental Therapeutics in Cancer, Jewish General Hospital, McGill University, Montreal, Canada Molecular Oncology Laboratory, McGill University, Montreal, Canada Dept of Chemistry, University of Quebec at Montreal, Canada Division of Hematology/Oncology, Jewish General Hospital, McGill University, Montreal, Canada * Corresponding author; email: jacques.galipeau{at}mcgill.ca. We hypothesized that a Granulocyte Macrophage Colony Stimulating Factor (GMCSF) and Interleukin (IL)15 fusokine (GIFT15) would possess greater immune stimulatory properties than their combined use. Unexpectedly, tumor cells engineered to secrete GIFT15 protein led to suppression of natural killer (NK) and NKT-cell recruitment in vivo, suggesting an unanticipated immune suppressive effect. We found GIFT15 to have pleiotropic effects on an array of immune competent cells. Amongst these, macrophages treated with GIFT15 secrete de novo the tissue inhibitor of metalloproteinase-2 (TIMP-2); activated matrix metalloproteinase-2 (MMP-2); transforming growth factor- (TGF-) as well as vascular endothelial growth factor (VEGF). We show that the GIFT15 fusokine has increased affinity for the chain component of the IL15R leading to aberrant signalling through the chain manifested by the hyperphosphorylation of STAT3 both in macrophages and splenocytes. Suppression of common chain-mediated STAT5 phosphorylation and blockade of the IL15-dependent IFN- response in mouse splenocytes was also observed. We tested GIFT15 as an immunosuppressor and demonstrated that it allowed engraftment of allogeneic B16F0 and human xenograft U87MG glioma cells in immunocompetent mice. Thus, GIFT15 defines a new class of fusokine which mediates pro-angiogenic and immunosuppressive effects via aberrant signalling by the IL15R in lymphomyeloid cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Rowley, A. Monie, C.-F. Hung, and T.-C. Wu Inhibition of Tumor Growth by NK1.1+ Cells and CD8+ T Cells Activated by IL-15 through Receptor {beta}/Common {gamma} Signaling in trans J. Immunol., December 15, 2008; 181(12): 8237 - 8247. [Abstract] [Full Text] [PDF]

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