Distinct Immunoregulatory Mechanisms in Mesenchymal Stem Cells: Role of the Cytokine Environment.
Mesenchymal stem cells (MSCs) represent a population of cells which have the ability to regulate reactivity of T and B lymphocytes by multiple mechanisms. The immunoregulatory activities of MSCs are strictly influenced by the cytokine environment. Here we show that two functionally distinct cytokines, interleukin-4 (IL-4) and interferon-γ (IFN-γ), significantly potentiate the ability of MSCs to inhibit IL-10 production by activated regulatory B cells (Bregs). However, MSCs in the presence of IL-4 or IFN-γ inhibit the IL-10 production by different mechanisms. Preincubation of MSCs with IFN-γ led to the suppression, but pretreatment with IL-4 of neither MSCs nor B cells resulted in the suppression of IL-10 production. The search for candidate regulatory molecules expressed in cytokine-treated MSCs revealed different patterns of the gene expression. Pretreatment of MSCs with IFN-γ, but not with IL-4, induced expression of indoleamine-2,3-dioxygenase, cyclooxygenase-2 and programmed cell death-ligand 1. To identify the molecule(s) responsible for the suppression of IL-10 production, we used specific inhibitors of the putative regulatory molecules. We found that indomethacine, an inhibitor of cyclooxygenase-2 (Cox-2) activity, completely abrogated the inhibition of IL-10 production in cultures containing MSCs and IFN-γ, but had no effect on the suppression in cell cultures containing MSCs and IL-4. The results show that MSCs can inhibit the response of B cells to one stimulus by different mechanisms in dependence on the cytokine environment and thus support the idea of the complexity of immunoregulatory action of MSCs.
Department of Transplantation Immunology, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Videnska 1083, 14220, Prague 4, Czech Republic. holan@biomed.cas.cz.|Department of Cell Biology, Faculty of Natural Science, Charles University, Vinicna 7, 12843, Prague 4, Czech Republic. holan@biomed.cas.cz.
Vladimir
0000-0002-2011-3390
V
Holan
Department of Transplantation Immunology, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Videnska 1083, 14220, Prague 4, Czech Republic.|Department of Cell Biology, Faculty of Natural Science, Charles University, Vinicna 7, 12843, Prague 4, Czech Republic.
Barbora
B
Hermankova
Department of Transplantation Immunology, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Videnska 1083, 14220, Prague 4, Czech Republic.|Department of Cell Biology, Faculty of Natural Science, Charles University, Vinicna 7, 12843, Prague 4, Czech Republic.
Pavla
P
Bohacova
Department of Transplantation Immunology, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Videnska 1083, 14220, Prague 4, Czech Republic.|Department of Cell Biology, Faculty of Natural Science, Charles University, Vinicna 7, 12843, Prague 4, Czech Republic.
Jan
J
Kossl
Department of Transplantation Immunology, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Videnska 1083, 14220, Prague 4, Czech Republic.|Department of Cell Biology, Faculty of Natural Science, Charles University, Vinicna 7, 12843, Prague 4, Czech Republic.
Milada
M
Chudickova
Department of Transplantation Immunology, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Videnska 1083, 14220, Prague 4, Czech Republic.|Department of Cell Biology, Faculty of Natural Science, Charles University, Vinicna 7, 12843, Prague 4, Czech Republic.
Michaela
M
Hajkova
Department of Transplantation Immunology, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Videnska 1083, 14220, Prague 4, Czech Republic.|Department of Cell Biology, Faculty of Natural Science, Charles University, Vinicna 7, 12843, Prague 4, Czech Republic.
Magdalena
M
Krulova
Department of Transplantation Immunology, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Videnska 1083, 14220, Prague 4, Czech Republic.
Alena
A
Zajicova
Department of Transplantation Immunology, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Videnska 1083, 14220, Prague 4, Czech Republic.|Department of Cell Biology, Faculty of Natural Science, Charles University, Vinicna 7, 12843, Prague 4, Czech Republic.
Eliska
E
Javorkova
D000818:Animals; D060151:B-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000187:drug effects / Q000276:immunology*; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines; C508598:IL4 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015850:Interleukin-6; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D051546:Cyclooxygenase 2
Cyclooxygenase 2; Cytokine environment; Gene expression; IFN-γ; IL-10; IL-4; Immunoregulation; Mesenchymal stem cells; Regulatory B cells
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