Restricted accessResearch articleFirst published online 2014-09
Umbilical Cord-Derived Mesenchymal Stem Cells Instruct Dendritic Cells to Acquire Tolerogenic Phenotypes Through the IL-6-Mediated Upregulation of SOCS1
The mechanisms responsible for the inhibitory effects of mesenchymal stem cells (MSCs) on dendritic cells (DCs) are still poorly understood. Our investigation of the potential signaling pathways revealed for the first time that human umbilical-cord-derived MSCs (UC-MSCs) instruct DCs to acquire tolerogenic phenotypes through the IL-6-mediated upregulation of SOCS1. This subset of MSC-DCs exhibited a tolerogenic pattern, with a clear decrease in the expression of co-stimulatory molecules and the capacity to stimulate CD3+ T cell proliferation and inflammatory factor secretion, and a significant increase in the production of inhibitory cytokine IL-10 and the ability to induce Treg cells and Th2 responses. Adoption of this tolerogenic pattern required the activation of SOCS1, which blocked DC maturation by impairing TLR4 signaling. The effects of UC-MSCs on SOCS1 activation were essentially mediated by the JAK-STAT pathway via IL-6 secretion. In summary, our data identify a new mechanism, involving the IL-6-mediated upregulation of SOCS1, by which UC-MSCs instruct DCs to acquire tolerogenic phenotypes.
Get full access to this article
View all access options for this article.
References
1.
PittengerMF, MackayAM, BeckSC, JaiswalRK, DouglasR, MoscaJD, MoormanMA, SimonettiDW, CraigS and MarshakDR. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284:143–147.
2.
ProckopDJ. (1997). Marrow stromal cells as stem cells for nonhematopoietic tissues. Science, 276:71–74.
3.
JorgensenC, DjouadF, ApparaillyF and NoelD. (2003). Engineering mesenchymal stem cells for immunotherapy. Gene Ther, 10:928–931.
4.
UccelliA, MorettaL and PistoiaV. (2008). Mesenchymal stem cells in health and disease. Nat Rev Immunol, 8:726–736.
5.
ZhaoRC, LiaoL and HanQ. (2004). Mechanisms of and perspectives on the mesenchymal stem cell in immunotherapy. J Lab Clin Med, 143:284–291.
6.
SpaggiariGM, CapobiancoA, BecchettiS, MingariMC and MorettaL. (2006). Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood, 107:1484–1490.
7.
Di NicolaM, Carlo-StellaC, MagniM, MilanesiM, LongoniPD, MatteucciP, GrisantiS and GianniAM. (2002). Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood, 99:3838–3843.
8.
KramperaM, GlennieS, DysonJ, ScottD, LaylorR, SimpsonE and DazziF. (2003). Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood, 101:3722–3729.
9.
BartholomewA, SturgeonC, SiatskasM, FerrerK, McIntoshK, PatilS, HardyW, DevineS, UckerD, et al. (2002). mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol, 30:42–48.
10.
Le BlancK, RasmussonI, SundbergB, GotherstromC, HassanM, UzunelM and RingdenO. (2004). Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet, 363:1439–1441.
11.
MeiselR, ZibertA, LaryeaM, GobelU, DaubenerW and DillooD. (2004). Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood, 103:4619–4621.
12.
RenG, ZhangL, ZhaoX, XuG, ZhangY, RobertsAI, ZhaoRC and ShiY. (2008). Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell, 2:141–150.
13.
PotianJA, AvivH, PonzioNM, HarrisonJS and RameshwarP. (2003). Veto-like activity of mesenchymal stem cells: functional discrimination between cellular responses to alloantigens and recall antigens. J Immunol, 171:3426–3434.
14.
TseWT, PendletonJD, BeyerWM, EgalkaMC and GuinanEC. (2003). Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation, 75:389–397.
15.
DjouadF, PlenceP, BonyC, TropelP, ApparaillyF, SanyJ, NoelD and JorgensenC. (2003). Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood, 102:3837–3844.
16.
BeythS, BorovskyZ, MevorachD, LiebergallM, GazitZ, AslanH, GalunE and RachmilewitzJ. (2005). Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood, 105:2214–2219.
17.
ZeddouM, BriquetA, RelicB, JosseC, MalaiseMG, GothotA, LechanteurC and BeguinYM. (2010). The umbilical cord matrix is a better source of mesenchymal stem cells (MSC) than the umbilical cord blood. Cell Biol Int, 34:693–701.
18.
BanasA, TerataniT, YamamotoY, TokuharaM, TakeshitaF, QuinnG, OkochiH and OchiyaT. (2007). Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Hepatology, 46:219–228.
19.
JinJD, WangHX, XiaoFJ, WangJS, LouX, HuLD, WangLS and GuoZK. (2008). A novel rich source of human mesenchymal stem cells from the debris of bone marrow samples. Biochem Biophys Res Commun, 376:191–195.
20.
LuLL, LiuYJ, YangSG, ZhaoQJ, WangX, GongW, HanZB, XuZS, LuYX, et al. (2006). Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica, 91:1017–1026.
SteinmanRM. (2003). The dendritic cell system and its role in immunogenicity. Annu Rev Immunol, 9:271–296.
23.
SteinmanRM, HawigerD and NussenzweigMC. (2003). Tolerogenic dendritic cells. Annu Rev Immunol, 21:685–711.
24.
ThomsonAW and RobbinsPD. (2008). Tolerogenic dendritic cells for autoimmune disease and transplantation. Ann Rheum Dis, 67 (Suppl. 3):iii90–iii96.
25.
ChornyA, Gonzalez-ReyE and GaneaD. (2006). Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo: therapeutic applications in autoimmunity and transplantation. Ann N Y Acad Sci, 1070:190–195.
26.
BenkhouchaM, Santiago-RaberML, SchneiterG, ChofflonM, FunakoshiH, NakamuraT and LalivePH. (2010). Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25+Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A, 107:6424–6429.
27.
FarquharCA, PatersonAM, CobboldSP, Garcia RuedaH, FairchildPJ, YatesSF, AdamsE, SaundersNJ, WaldmannH and NolanKF. (2010). Tolerogenicity is not an absolute property of a dendritic cell. Eur J Immunol, 40:1728–1737.
28.
BoksMA, Kager-GroenlandJR, HaasjesMS, ZwagingaJJ, van HamSM and ten BrinkeA. (2012). IL-10-generated tolerogenic dendritic cells are optimal for functional regulatory T cell induction—a comparative study of human clinical-applicable DC. Clin Immunol, 142:332–342.
29.
ChenL, ZhangW, YueH, HanQ, ChenB, ShiM, LiJ, LiB, YouS, ShiY and ZhaoRC. (2007). Effects of human mesenchymal stem cells on the differentiation of dendritic cells from CD34+ cells. Stem Cells Dev, 16:719–731.
30.
ChiesaS, MorbelliS, MorandoS, MassolloM, MariniC, BertoniA, FrassoniF, BartolomeST, GambucetiG, TraggiaiE and UccelliA. (2011). Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells. Proc Natl Acad Sci U S A, 108:17384–17389.
31.
ZhangB, LiuR, ShiD, LiuX, ChenY, DouX, ZhuX, LuC, LiangW, et al. (2009). Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2-dependent regulatory dendritic cell population. Blood, 113:46–57.
32.
ZhangW, GeW, LiC, YouS, LiaoL, HanQ, DengW and ZhaoRC. (2004). Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells. Stem Cells Dev, 13:263–271.
33.
LiYP, PaczesnyS, LauretE, PoiraultS, BordigoniP, MekhloufiF, HequetO, BertrandY, Ou-YangJP, et al. (2008). Human mesenchymal stem cells license adult CD34+ hemopoietic progenitor cells to differentiate into regulatory dendritic cells through activation of the Notch pathway. J Immunol, 180:1598–1608.
34.
O'SheaJJ, GadinaM and SchreiberRD. (2002). Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell, 109 (Suppl.):S121–S131.
35.
StarrR, WillsonTA, VineyEM, MurrayLJ, RaynerJR, JenkinsBJ, GondaTJ, AlexanderWS, MetcalfD, NicolaNA and HiltonDJ. (1997). A family of cytokine-inducible inhibitors of signalling. Nature, 87:917–921.
36.
StarrR, MetcalfD, ElefantyAG, BryshaM, WillsonTA, NicolaNA, HiltonDJ and AlexanderWS. (1998). Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1. Proc Natl Acad Sci U S A, 95:14395–14399.
37.
HensonSM, MacaulayR, Kiani-AlikhanS and AkbarAN. The use of the inhibitory receptors for modulating the immune responses. Curr Pharm Des, 14:2643–2650.
38.
TanakaK. (2008). Loss of suppressor of cytokine signaling-1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN on STAT3 and Smads. J Immunol, 180:3746–3756.
39.
HanadaT, YoshidaH, KatoS, TanakaK, MasutaniK, TsukadaJ, NomuraY, MimataH, KuboM and YoshimuraA. (2003). Suppressor of cytokine signaling-1 is essential for suppressing dendritic cell activation and systemic autoimmunity. Immunity, 19:437–450.
40.
JacksonSH, YuCR, MahdiRM, EbongS and EgwuaguCE. (2004). Dendritic cell maturation requires STAT1 and is under feedback regulation by suppressors of cytokine signaling. J Immunol, 172:2307–2315.
41.
ShenL, Evel-KablerK, StrubeR and ChenSY. (2004). Silencing of SOCS1 enhances antigen presentation by dendritic cells and antigen-specific anti-tumor immunity. Nat Biotechnol, 22:1546–1553.
42.
SatouR, MiyataK, Gonzalez-VillalobosRA, IngelfingerJR, NavarLG and KoboriH. (2012). Interferon-gamma biphasically regulates angiotensinogen expression via a JAK-STAT pathway and suppressor of cytokine signaling 1 (SOCS1) in renal proximal tubular cells. FASEB J, 26:1821–1830.
43.
TamiyaT, KashiwagiI, TakahashiR, YasukawaH and YoshimuraA. (2011). Suppressors of cytokine signaling (SOCS) proteins and JAK/STAT pathways: regulation of T-cell inflammation by SOCS1 and SOCS3. Arterioscler Thromb Vasc Biol, 31:980–985.
44.
KuboM, HanadaT and YoshimuraA. (2003). Suppressors of cytokine signaling and immunity. Nat Immunol, 4:1169–1176.
45.
AlexanderWS and HiltonDJ. (2004). The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Annu Rev Immunol, 22:503–529.
46.
SubramanyaS, ArmantM, SalkowitzJR, NyakerigaAM, HaridasV, HasanM, BansalA, GoepfertPA, WynnKK, et al. (2010). Enhanced induction of HIV-specific cytotoxic T lymphocytes by dendritic cell-targeted delivery of SOCS-1 siRNA. Mol Ther, 18:2028–2037.
47.
ManettiR, GerosaF, GiudiziMG, BiagiottiR, ParronchiP, PiccinniMP, SampognaroS, MaggiE, RomagnaniS and TrinchieriG. (1994). Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones. J Exp Med, 179:1273–1283.
48.
KinjyoI, HanadaT, Inagaki-OharaK, MoriH, AkiD, OhishiM, YoshidaH, KuboM and YoshimuraA. (2002). SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity, 17:583–591.
49.
NakagawaR, NakaT, TsutsuiH, FujimotoM, KimuraA, AbeT, SekiE, SatoS, TakeuchiO, et al. (2002). SOCS-1 participates in negative regulation of LPS responses. Immunity, 17:677–687.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
