MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2.
Various studies analyzed the inhibitory effect exerted by mesenchymal stem cells (MSCs) on cells of the innate or acquired immunity. Myeloid dendritic cells (DCs) are also 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 granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (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 E(2) (PGE(2)). Thus, addition of the PGE(2) inhibitor NS-398 restored DC differentiation and function. Moreover, PGE(2) directly added to cultures of monocytes blocked their differentiation toward 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 PGE(2) and not IL-6 represents the key inhibitory mediator. Indeed, NS-398 inhibited PGE(2) production and restored DC differentiation with no effect on IL-6 production. These data emphasize the role of MSCs in inhibiting early DC maturation and identifying the molecular mechanisms responsible for the inhibitory effect.
Spaggiari
Grazia Maria
GM
Istituto Giannina Gaslini, Largo Gerolamo Gaslini 5, Genoa, Italy.
Abdelrazik
Heba
H
Becchetti
Flavio
F
Moretta
Lorenzo
L
D015703:Antigens, CD / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002648:Child; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D009000:Monocytes / Q000166:cytology*; D009578:Nitrobenzenes / Q000494:pharmacology; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology; D000093242:Interleukin-6 Inhibitors
D015703:Antigens, CD; D015232:Dinoprostone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015847:Interleukin-4; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016173:Macrophage Colony-Stimulating Factor; D009578:Nitrobenzenes; D011448:Prostaglandin Antagonists; D013449:Sulfonamides; D000093242:Interleukin-6 Inhibitors; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide