SEARCH:   Advanced

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 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 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 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. Related Collections Immunobiology Transplantation Signal Transduction Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  TRANSPLANTATION A GMCSF and IL-15 fusokine leads to paradoxical immunosuppression in vivo via asymmetrical JAK/STAT signaling through the IL-15 receptor complex Moutih Rafei1, Jian Hui Wu2, Borhane Annabi3, Laurence Lejeune1, Moïra François1, and Jacques Galipeau1,4 1 The Montreal Centre for Experimental Therapeutics in Cancer, Jewish General Hospital, McGill University, Montreal, QC, 2 Molecular Oncology Laboratory, McGill University, Montreal, QC; 3 Department of Chemistry, University of Quebec at Montreal (UQAM), Montreal, QC; and 4 Division of Hematology/Oncology, Jewish General Hospital, McGill University, Montreal, QC We hypothesized that a granulocyte macrophage colony-stimulating factor (GMCSF) and interleukin 15 (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. Among 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-ß (TGF-ß); as well as vascular endothelial growth factor (VEGF). We show that the GIFT15 fusokine has increased affinity for the chain component of the IL-15R, leading to aberrant signaling through the ß chain manifested by the hyperphosphorylation of STAT3 both in macrophages and splenocytes. Suppression of common chain–mediated STAT5 phosphorylation and blockade of the IL-15–dependent IFN- response in mouse splenocytes were also observed. We tested GIFT15 as an immunosuppressor and demonstrated that it allowed engraftment of allogeneic B16F0 and human xenograft U87GM glioma cells in immunocompetent mice. Thus, GIFT15 defines a new class of fusokine that mediates proangiogenic and immunosuppressive effects via aberrant signaling by the IL-15R in lymphomyeloid cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Copyright © 2007 by American Society of Hematology         Online ISSN: 1528-0020