Submitted February 5, 2009
Accepted April 15, 2009
Mesenchymal stem cells (MSC) inhibit monocyte-derived dendritic cell (DC) maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2
Grazia Maria Spaggiari, Heba Abdelrazik, Flavio Becchetti, and Lorenzo Moretta*
Istituto Giannina Gaslini, Genova, Italy
Dipartimento di Medicina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Universita di Genova, Genova, Italy
* Corresponding author; email: lorenzomoretta{at}ospedale-gaslini.ge.it.
Various studies analyzed the inhibitory effect exerted by mesenchymal stem cells (MSC) on cells of the innate or acquired immunity. Also myeloid dendritic cells (DCs) are susceptible to such inhibition. In this study, we show that MSCs strongly inhibit DC generation from peripheral blood monocytes. In the presence of MSCs, monocytes supplemented with GM-CSF and IL-4 did not acquire the surface phenotype typical of immature (CD14-, CD1a+) or mature (CD80+, CD86+, CD83+) DCs, failed to produce IL-12 and did not induce T cell activation or proliferation. Analysis of the molecular mechanism(s) responsible for the inhibitory effect revealed a major role of prostaglandin E2 (PGE2). Thus, addition of the PGE2 inhibitor NS-398 restored DC differentiation and function. Moreover, PGE2 directly added to cultures of monocytes blocked their differentiation towards DCs in a manner similar to MSCs. Although IL-6 has been proposed to play a role in MSC-mediated inhibition of DC differentiation, our data indicate that PGE2 and not IL-6 represents the key inhibitory mediator. Indeed, NS-398 inhibited PGE2 production and restored DC differentiation with no effect on IL-6 production. These data emphasize the role of MSC in inhibiting early DC maturation and identify the molecular mechanisms responsible for the inhibitory effect.
