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TISSUE-SPECIFIC STEM CELLS |
aInstitut National de la Santé et de la Recherche Médicale, U 844, Montpellier, France;
bUniversité Montpellier, Unité de Formation et de Recherche de Médecine, Montpellier, France;
cCentre Hospitalier Universitaire Montpellier, Hôpital Lapeyronie, Unité Clinique d'Immuno-Rhumatologie, Montpellier, France
Key Words. Stromal cells • Tolerance/suppression/anergy • Cytokines
Correspondence: Danièle Noël, Ph.D., Institut National de la Santé et de la Recherche Médicale, U 844, Hôpital Saint-Eloi, Bât INM, 80 Avenue Augustin Fliche, F-34091 Montpellier, France. Telephone: 33 (0) 4 99 63 60 26; Fax: 33 (0) 4 99 63 60 20; e-mail: noel{at}montp.inserm.fr
Received August 31, 2006;
accepted for publication May 9, 2007.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLS EXPRESS May 17, 2007.
Mesenchymal stem cells (MSC) are of particular interest for their potential clinical use in tissue engineering as well as for their capacity to reduce the incidence and severity of graft-versus-host disease in allogeneic transplantation. We have previously shown that MSC-mediated immune suppression acts via the secretion of soluble factor(s) induced upon stimulation. The aim of this study was to identify the molecule(s) involved and the underlying mechanism(s). We show that murine MSC secrete high levels of interleukin (IL)-6 and vascular endothelial growth factor, which are directly correlated to the inhibition of T-cell proliferation. The T-cell activation is partially restored upon addition of a neutralizing anti-IL-6 antibody or the prostaglandin E2 inhibitor indomethacin. Interestingly, no indoleamine 2,3-dioxygenase activity was detected in our conditions. Instead, we show that MSC reduce the expression of major histocompatibility complex class II, CD40, and CD86 costimulatory molecules on mature dendritic cells (DC), which was responsible for a decrease in T-cell proliferation. Moreover, we show that the differentiation of bone marrow progenitors into DC cultured with conditioned supernatants from MSC was partly inhibited through the secretion of IL-6. Altogether, these data suggest that IL-6 is involved in the immunoregulatory mechanism mediated by MSC through a partial inhibition of DC differentiation but is probably not the main mechanism.
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