Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide.
Mesenchymal stem cells (MSCs) can become potently immunosuppressive through unknown mechanisms. We found that the immunosuppressive function of MSCs is elicited by IFNgamma and the concomitant presence of any of three other proinflammatory cytokines, TNFalpha, IL-1alpha, or IL-1beta. These cytokine combinations provoke the expression of high levels of several chemokines and inducible nitric oxide synthase (iNOS) by MSCs. Chemokines drive T cell migration into proximity with MSCs, where T cell responsiveness is suppressed by nitric oxide (NO). This cytokine-induced immunosuppression was absent in MSCs derived from iNOS(-/-) or IFNgammaR1(-/-) mice. Blockade of chemokine receptors also abolished the immunosuppression. Administration of wild-type MSCs, but not IFNgammaR1(-/-) or iNOS(-/-) MSCs, prevented graft-versus-host disease in mice, an effect reversed by anti-IFNgamma or iNOS inhibitors. Wild-type MSCs also inhibited delayed-type hypersensitivity, while iNOS(-/-) MSCs aggravated it. Therefore, proinflammatory cytokines are required to induce immunosuppression by MSCs through the concerted action of chemokines and NO.
Ren
Guangwen
G
Department of Molecular Genetics, Microbiology and Immunology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 661 Hoes Lane, Piscataway, NJ 08854, USA.
Zhang
Liying
L
Zhao
Xin
X
Xu
Guangwu
G
Zhang
Yingyu
Y
Roberts
Arthur I
AI
Zhao
Robert Chunhua
RC
Shi
Yufang
Y
D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018925:Chemokines / Q000502:physiology*; D016207:Cytokines / Q000494:pharmacology; D006086:Graft vs Host Disease / Q000517:prevention & control; D006968:Hypersensitivity, Delayed / Q000517:prevention & control; D007108:Immune Tolerance / Q000276:immunology*; D007371:Interferon-gamma / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D017471:Receptors, Interferon / Q000235:genetics; D000096743:Interferon gamma Receptor
D018925:Chemokines; D016207:Cytokines; D007371:Interferon-gamma; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor