title: Suppression of IL-10 production by activated B cells via a cell contact-dependent cyclooxygenase-2 pathway upregulated in IFN-γ-treated mesenchymal stem cells.
abstract: The immunoregulatory properties of mesenchymal stem cells (MSCs) have been well documented in various models in vitro and in vivo. Furthermore, a population of regulatory B cells (Bregs) that produce relatively high concentrations of IL-10 has been recently described. To study the relationship between MSCs and Bregs, we analyzed the effects of MSCs on IL-10 production by lipopolysaccharide (LPS)-activated mouse B cells. The production of IL-10 by B cells remained preserved in the presence of MSCs and was even significantly enhanced by IFN-γ. However, the production of IL-10 was strongly suppressed in cultures containing MSCs and IFN-γ. Preincubation of MSCs, but not of B cells, with IFN-γ induced the suppression of IL-10 secretion in cultures containing MSCs and B cells. The supernatants from IFN-γ-treated MSCs had no inhibitory effect, and the suppression of IL-10 production was abrogated if the MSCs and B cells were separated in a transwell system. Analysis of the gene expression of IFN-γ- or IFN-γ and LPS-treated MSCs revealed a strong upregulation of genes for indoleamine-2,3-dioxygenase (IDO), cyclooxygenase-2 (Cox-2) and programmed cell death-ligand 1 (PD-L1). While the inhibition of IDO activity or the inclusion of the neutralization monoclonal antibody anti-PD-L1 did not abrogate the suppression, indomethacin, an inhibitor of Cox-2, completely inhibited the MSC-mediated suppression of IL-10 production. Accordingly, the production of IL-10 by B cells was inhibited by exogenous prostaglandin E2. The results thus suggest that IFN-γ-treated MSCs strongly inhibit IL-10 production by activated B cells by a mechanism requiring cell contact and involving the Cox-2 pathway.
authors.affiliation: Department of Transplantation Immunology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague, Czech Republic; Faculty of Natural Science, Charles University, Albertov 6, 128 40 Prague, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Hermankova
authors.affiliation: Department of Transplantation Immunology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague, Czech Republic.
authors.forename: Alena
authors.initials: A
authors.lastname: Zajicova
authors.affiliation: Department of Transplantation Immunology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague, Czech Republic; Faculty of Natural Science, Charles University, Albertov 6, 128 40 Prague, Czech Republic.
authors.forename: Eliska
authors.initials: E
authors.lastname: Javorkova
authors.affiliation: Department of Transplantation Immunology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague, Czech Republic; Faculty of Natural Science, Charles University, Albertov 6, 128 40 Prague, Czech Republic.
authors.forename: Milada
authors.initials: M
authors.lastname: Chudickova
authors.affiliation: Department of Transplantation Immunology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague, Czech Republic; Faculty of Natural Science, Charles University, Albertov 6, 128 40 Prague, Czech Republic.
authors.forename: Peter
authors.initials: P
authors.lastname: Trosan
authors.affiliation: Department of Transplantation Immunology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague, Czech Republic; Faculty of Natural Science, Charles University, Albertov 6, 128 40 Prague, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Hajkova
authors.affiliation: Department of Transplantation Immunology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague, Czech Republic; Faculty of Natural Science, Charles University, Albertov 6, 128 40 Prague, Czech Republic.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Krulova
authors.affiliation: Department of Transplantation Immunology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague, Czech Republic; Faculty of Natural Science, Charles University, Albertov 6, 128 40 Prague, Czech Republic. Electronic address: holan@biomed.cas.cz.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Holan
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015194:Diffusion Chambers, Culture; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology; D007213:Indomethacin / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D061251:Primary Cell Culture; D015398:Signal Transduction
chemical_list: D057134:Antibodies, Neutralizing; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D017077:Culture Media, Conditioned; D016861:Cyclooxygenase Inhibitors; C556062:IL10 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008070:Lipopolysaccharides; D016753:Interleukin-10; D007371:Interferon-gamma; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D007213:Indomethacin
keywords: B cells; Cyclooxygenase-2; IL-10 production; Immunosuppression; Mesenchymal stem cells