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Blood, 15 December 2008, Vol. 112, No. 13, pp. 4991-4998. Prepublished online as a Blood First Edition Paper on September 23, 2008; DOI 10.1182/blood-2008-07-166892. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-07-166892v1 112/13/4991    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 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. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Mesenchymal stromal cell–derived CCL2 suppresses plasma cell immunoglobulin production via STAT3 inactivation and PAX5 induction Moutih Rafei1, Jeremy Hsieh1, Simon Fortier2, MengYang Li1, Shala Yuan1, Elena Birman1, Kathy Forner1, Marie-Noelle Boivin1, Karen Doody3, Michel Tremblay3, Borhane Annabi2, and Jacques Galipeau1,4 1 Montreal Centre for Experimental Therapeutics in Cancer and 2 Laboratoire d'Oncologie Moléculaire, Département de Chimie, Centre BIOMED, Université du Québec à Montréal, Montreal, QC; 3 McGill Cancer Centre and Department of Biochemistry, McGill University, Montreal, QC; and 4 Division of Hematology/Oncology, Jewish General Hospital, McGill University, Montreal, QC We demonstrate that the secretome of mesenchymal stromal cells (MSCs) suppresses plasma cell (PC) immunoglobulin (Ig) production, induces plasmablast proliferation, and leads to interleukin-10–mediated blockade in vitro. We found that these effects are the result of MSC-derived CC chemokine ligands CCL2 and CCL7. More specifically, MSCs further processed these CC chemokines by the activity of matrix metalloproteinases (MMPs), leading to the generation of proteolytically processed antagonistic CCL2 variant. Neutralizing CCL2 or inhibiting MMP enzymatic activity abolished the PC-suppressive effect of MSCs. We also observed that MMP-processed CCL2 suppresses signal transducer and activator of transcription 3 (STAT3) activation in PC. As a result, the transcription factor PAX5 is induced, thus explaining the inhibition of Ig synthesis. The absence of inhibitory effects by MSC on the humoral response of CCR2–/– mice to xenoantigen suggests that MMP-cleaved CCL2/CCR2 interaction as well as downstream phosphatase activity is necessary for antagonistic effect. We tested syngeneic MSCs in hemophilic B6 mice with predeveloped antihuman factor VIII (hFVIII) antibodies and demonstrated a robust decrease in hFVIII-specific IgG levels. Thus, MSCs may play a role in modulating Ig production by PCs via MMP processing of CCL2 and may represent an appealing cell therapy approach for pathologic humoral responses. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Rafei, P. M. Campeau, A. Aguilar-Mahecha, M. Buchanan, P. Williams, E. Birman, S. Yuan, Y. K. Young, M.-N. Boivin, K. Forner, et al. Mesenchymal Stromal Cells Ameliorate Experimental Autoimmune Encephalomyelitis by Inhibiting CD4 Th17 T Cells in a CC Chemokine Ligand 2-Dependent Manner J. Immunol., May 15, 2009; 182(10): 5994 - 6002. [Abstract] [Full Text] [PDF]

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