Proinflammatory stimuli induce galectin-9 in human mesenchymal stromal cells to suppress T-cell proliferation

TY - JOUR

T1 - Proinflammatory stimuli induce galectin-9 in human mesenchymal stromal cells to suppress T-cell proliferation

AU - Gieseke, Friederike

AU - Kruchen, Anne

AU - Tzaribachev, Nikolay

AU - Bentzien, Frank

AU - Dominici, Massimo

AU - Müller, Ingo

N1 - © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PY - 2013/10/1

Y1 - 2013/10/1

N2 - Human multipotent mesenchymal stromal cells (MSCs) are clinically applied to treat autoimmune diseases and graft-versus-host disease due to their immunomodulatory properties. Several molecules have been identified to mediate these effects, including constitutively expressed galectin-1. However, there are indications in the literature that MSCs exert enhanced immunosuppressive functions after interaction with an inflammatory environment. Therefore, we analyzed how inflammatory stimuli influence the expression of the galectin network in MSCs and functionally tested the relevance for the immunomodulatory effects of MSCs. We found that galectin-9 was strongly induced in MSCs upon interaction with activated PBMCs. Proinflammatory cytokines, such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), and also ligands of the Toll-like receptors (TLRs) TLR2, TLR3, and TLR4 elicited similar induction of galectin-9 in activated PBMCs. Galectin-9 was not only upregulated intracellularly, but also released by MSCs in significant amounts into the supernatant after exposure to proinflammatory stimuli. In proliferation assays, MSCs with a galectin-9 knockdown lost a significant portion of their antiproliferative effects on T cells. In conclusion, we found that unlike constitutively expressed galectin-1, galectin-9 is induced by several proinflammatory stimuli and released by MSCs. Thus, galectin-9 contributes to the inducible immunomodulatory functions of MSCs.

AB - Human multipotent mesenchymal stromal cells (MSCs) are clinically applied to treat autoimmune diseases and graft-versus-host disease due to their immunomodulatory properties. Several molecules have been identified to mediate these effects, including constitutively expressed galectin-1. However, there are indications in the literature that MSCs exert enhanced immunosuppressive functions after interaction with an inflammatory environment. Therefore, we analyzed how inflammatory stimuli influence the expression of the galectin network in MSCs and functionally tested the relevance for the immunomodulatory effects of MSCs. We found that galectin-9 was strongly induced in MSCs upon interaction with activated PBMCs. Proinflammatory cytokines, such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), and also ligands of the Toll-like receptors (TLRs) TLR2, TLR3, and TLR4 elicited similar induction of galectin-9 in activated PBMCs. Galectin-9 was not only upregulated intracellularly, but also released by MSCs in significant amounts into the supernatant after exposure to proinflammatory stimuli. In proliferation assays, MSCs with a galectin-9 knockdown lost a significant portion of their antiproliferative effects on T cells. In conclusion, we found that unlike constitutively expressed galectin-1, galectin-9 is induced by several proinflammatory stimuli and released by MSCs. Thus, galectin-9 contributes to the inducible immunomodulatory functions of MSCs.

KW - Autoimmune Diseases

KW - Cell Proliferation

KW - Cells, Cultured

KW - Galectins

KW - Humans

KW - Immunosuppression

KW - Inflammation

KW - Interferon-gamma

KW - Mesenchymal Stem Cell Transplantation

KW - Mesenchymal Stromal Cells

KW - RNA, Small Interfering

KW - T-Lymphocytes

KW - Toll-Like Receptors

KW - Tumor Necrosis Factor-alpha

KW - Up-Regulation

U2 - 10.1002/eji.201343335

DO - 10.1002/eji.201343335

M3 - SCORING: Journal article

C2 - 23817958

VL - 43

SP - 2741

EP - 2749

JO - EUR J IMMUNOL

JF - EUR J IMMUNOL

SN - 0014-2980

IS - 10

ER -