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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.
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Submitted July 7, 2008
Accepted August 31, 2008
Mesenchymal stromal cell derived CCL2 suppresses plasma cell immunoglobulin production via STAT3 inactivation and PAX5 induction
Moutih Rafei, Jeremy Hiseh, Simon Fortier, MengYang Li, Shala Yuan, Elena Birman, Kathy Forner, Marie-Noelle Boivin, Karen Doody, Michel Tremblay, Borhane Annabi, and Jacques Galipeau*
The Montreal Center for Experimental Therapeutics in Cancer, Montreal, Quebec, Canada
Laboratoire d'Oncologie Moleculaire, Departement de Chimie, Centre BIOMED, Universite du Quebec a Montreal, Montreal, Quebec, Canada
Department of Biochemistry, McGill Cancer Centre, McGill University, Montreal, Quebec, Canada
Division of Hematology/Oncology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
* Corresponding author; email: jacques.galipeau{at}mcgill.ca.
We demonstrate that the secretome of mesenchymal stromal cells (MSCs) suppresses plasma cell (PC) immunoglobulin production, induces plasmablast proliferation, and leads to IL10-mediated blockade in vitro. We found that these effects are due to MSC-derived CC-chemokines CCL2 and CCL7. More specifically, we found that 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 STAT3 activation in PC. As a result, the transcription factor PAX5 is induced thus explaining the inhibition of immunoglobulin 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 pre-developed anti-human Factor VIII (hFVIII) antibodies and demonstrated a robust decrease in hFVIII-specific IgG levels. Thus, marrow resident MSCs may play a physiological role in modulating Ig production by PCs via MMP processing of paracrine CCL2 secretion and may represent an appealing cell therapy approach for pathological humoral responses.
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