Species Variation in the Mechanisms of Mesenchymal Stem Cell-Mediated Immunosuppression
Tóm tắt
Bone marrow-derived mesenchymal stem cells (MSCs) hold great promise for treating immune disorders because of their immunoregulatory capacity, but the mechanism remains controversial. As we show here, the mechanism of MSC-mediated immunosuppression varies among different species. Immunosuppression by human- or monkey-derived MSCs is mediated by indoleamine 2,3-dioxygenase (IDO), whereas mouse MSCs utilize nitric oxide, under the same culture conditions. When the expression of IDO and inducible nitric oxide synthase (iNOS) were examined in human and mouse MSCs after stimulation with their respective inflammatory cytokines, we found that human MSCs expressed extremely high levels of IDO, and very low levels of iNOS, whereas mouse MSCs expressed abundant iNOS and very little IDO. Immunosuppression by human MSCs was not intrinsic, but was induced by inflammatory cytokines and was chemokine-dependent, as it is in mouse. These findings provide critical information about the immunosuppression of MSCs and for better application of MSCs in treating immune disorders.
Disclosure of potential conflicts of interest is found at the end of this article.
Từ khóa
Tài liệu tham khảo
Xu, 2007, Immunosuppressive properties of cloned bone marrow mesenchymal stem cells, Cell Res, 17, 240, 10.1038/cr.2007.4
Le Blanc, 2008, Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: A phase II study, Lancet, 371, 1579, 10.1016/S0140-6736(08)60690-X
Le Blanc, 2004, Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells, Lancet, 363, 1439, 10.1016/S0140-6736(04)16104-7
Burt, 2008, Clinical applications of blood-derived and marrow-derived stem cells for nonmalignant diseases, JAMA, 299, 925, 10.1001/jama.299.8.925
Parekkadan, 2008, Bone marrow-derived mesenchymal stem cells ameliorate autoimmune enteropathy independent of regulatory T cells, Stem Cells, 26, 1913, 10.1634/stemcells.2007-0790
Ren, 2008, Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide, Cell Stem Cell, 2, 141, 10.1016/j.stem.2007.11.014
Nasef, 2007, Identification of IL-10 and TGF-beta transcripts involved in the inhibition of T-lymphocyte proliferation during cell contact with human mesenchymal stem cells, Gene Expr, 13, 217, 10.3727/000000006780666957
Di Nicola, 2002, Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli, Blood, 99, 3838, 10.1182/blood.V99.10.3838
Aggarwal, 2005, Human mesenchymal stem cells modulate allogeneic immune cell responses, Blood, 105, 1815, 10.1182/blood-2004-04-1559
Sato, 2007, Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells, Blood, 109, 228, 10.1182/blood-2006-02-002246
Meisel, 2004, Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation, Blood, 103, 4619, 10.1182/blood-2003-11-3909
Djouad, 2003, Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals, Blood, 102, 3837, 10.1182/blood-2003-04-1193
Stamler, 1992, Biochemistry of nitric oxide and its redox-activated forms, Science, 258, 1898, 10.1126/science.1281928
Edwards, 2007, New perspectives on the mechanisms through which nitric oxide may affect learning and memory processes, Neurosci Biobehav Rev, 31, 413, 10.1016/j.neubiorev.2006.11.001
Murad, 2006, Shattuck Lecture. Nitric oxide and cyclic GMP in cell signaling and drug development, N Engl J Med, 355, 2003, 10.1056/NEJMsa063904
Niedbala, 2006, Role of nitric oxide in the regulation of T cell functions, Ann Rheum Dis, 65, iii37
Muller, 2007, Indoleamine 2,3-dioxygenase in immune suppression and cancer, Curr Cancer Drug Targets, 7, 31, 10.2174/156800907780006896
Munn, 2005, GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase, Immunity, 22, 633, 10.1016/j.immuni.2005.03.013
Forouzandeh, 2008, Differential immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO) on primary human CD4(+) and CD8(+) T cells, Mol Cell Biochem, 309, 1, 10.1007/s11010-007-9635-y
Wang, 2006, Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35, J Biol Chem, 281, 22021, 10.1074/jbc.M603503200
Ren, 2008, Apoptotic cells induce immunosuppression through dendritic cells: Critical roles of IFN-gamma and nitric oxide, J Immunol, 181, 3277, 10.4049/jimmunol.181.5.3277
Shi, 1993, A rapid, multiwell colorimetric assay for chemotaxis, J Immunol Methods, 164, 149, 10.1016/0022-1759(93)90307-S
Schneemann, 2002, Species differences in macrophage NO production are important, Nat Immunol, 3, 102, 10.1038/ni0202-102a
Jungi, 1996, Inducible nitric oxide synthase of macrophages. Present knowledge and evidence for species-specific regulation, Vet Immunol Immunopathol, 54, 323, 10.1016/S0165-2427(96)05690-5
Ryan, 2007, Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells, Clin Exp Immunol, 149, 353, 10.1111/j.1365-2249.2007.03422.x
Spaggiari, 2008, Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: Role of indoleamine 2,3-dioxygenase and prostaglandin E2, Blood, 111, 1327, 10.1182/blood-2007-02-074997
Munn, 2007, Indoleamine 2,3-dioxygenase and tumor-induced tolerance, J Clin Invest, 117, 1147, 10.1172/JCI31178
Grohmann, 2002, CTLA-4-Ig regulates tryptophan catabolism in vivo, Nat Immunol, 3, 1097, 10.1038/ni846
Mellor, 2004, IDO expression by dendritic cells: Tolerance and tryptophan catabolism, Nat Rev Immunol, 4, 762, 10.1038/nri1457
Hulkower, 1993, Expression of CSF-1, c-fms, and MCP-1 in the central nervous system of rats with experimental allergic encephalomyelitis, J Immunol, 150, 2525, 10.4049/jimmunol.150.6.2525
Uyttenhove, 2003, Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase, Nat Med, 9, 1269, 10.1038/nm934
Liu, 2006, Sleeping Beauty-based gene therapy with indoleamine 2,3-dioxygenase inhibits lung allograft fibrosis, FASEB J, 20, 2384, 10.1096/fj.06-6228fje
Morelli, 2007, Tolerogenic dendritic cells and the quest for transplant tolerance, Nat Rev Immunol, 7, 610, 10.1038/nri2132
Mackler, 2003, Indoleamine 2,3-dioxygenase is regulated by IFN-gamma in the mouse placenta during Listeria monocytogenes infection, J Immunol, 170, 823, 10.4049/jimmunol.170.2.823
Chon, 1996, Cooperative role of interferon regulatory factor 1 and p91 (STAT1) response elements in interferon-gamma-inducible expression of human indoleamine 2,3-dioxygenase gene, J Biol Chem, 271, 17247, 10.1074/jbc.271.29.17247
Fujigaki, 2001, Lipopolysaccharide induction of indoleamine 2,3-dioxygenase is mediated dominantly by an IFN-gamma-independent mechanism, Eur J Immunol, 31, 2313, 10.1002/1521-4141(200108)31:8<2313::AID-IMMU2313>3.0.CO;2-S
Weinberg, 1995, Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): Analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages, Blood, 86, 1184, 10.1182/blood.V86.3.1184.1184
Albina, 1995, On the expression of nitric oxide synthase by human macrophages. Why NO? NO?, J Leukoc Biol, 58, 643, 10.1002/jlb.58.6.643
Denis, 1994, Human monocytes/macrophages: NO or no NO?, J Leukoc Biol, 55, 682, 10.1002/jlb.55.5.682
Geller, 1993, Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes, Proc Natl Acad Sci U S A, 90, 3491, 10.1073/pnas.90.8.3491