title: Soluble Tumor Necrosis Factor Receptor 1 Released by Skin-Derived Mesenchymal Stem Cells Is Critical for Inhibiting Th17 Cell Differentiation.
abstract: T helper 17 (Th17) cells play an important role in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Th17 cell differentiation from naïve T cells can be induced in vitro by the cytokines transforming growth factor β1 and interleukin-6. However, it remains unclear whether other regulatory factors control the differentiation of Th17 cells. Mesenchymal stem cells (MSCs) have emerged as a promising candidate for inhibiting Th17 cell differentiation and autoimmune diseases. Despite the fact that several molecules have been linked to the immunomodulatory function of MSCs, many other key MSC-secreted regulators that are involved in inhibiting Th17 cell polarization are ill-defined. In this study, we demonstrated that the intraperitoneal administration of skin-derived MSCs (S-MSCs) substantially ameliorated the development of EAE in mice. We found that the proinflammatory cytokine tumor necrosis factor (TNF)-α, a key mediator in the pathophysiology of MS and EAE, was capable of promoting Th17 cell differentiation. Moreover, under inflammatory conditions, we demonstrated that S-MSCs produced high amounts of soluble TNF receptor 1 (sTNFR1), which binds TNF-α and antagonizes its function. Knockdown of sTNFR1 in S-MSCs decreased their inhibitory effect on Th17 cell differentiation ex vivo and in vivo. Thus, our data identified sTNFR1 and its target TNF-α as critical regulators for Th17 cell differentiation, suggesting a previously unrecognized mechanism for MSC therapy in Th17-mediated autoimmune diseases.
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Fang
authors.initials: F
authors.lastname: Ke
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Zhaoyuan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Sha
authors.initials: S
authors.lastname: Yan
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Zhenyao
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Bai
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Fangzhou
authors.initials: F
authors.lastname: Lou
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China honglin.wang@sjtu.edu.cn.
authors.forename: Honglin
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D009103:Multiple Sclerosis / Q000235:genetics* / Q000473:pathology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000096:biosynthesis / Q000235:genetics*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D047888:Receptors, Tumor Necrosis Factor, Type I; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha
keywords: Autoimmune disease; Differentiation; T cells; Tissue-specific stem cells
references.citation: J Cell Sci. 2006 Jun 1;119(Pt 11):2204-13
references.pmid: 16684817
references.citation: J Immunol. 2006 Jun 15;176(12):7768-74
references.pmid: 16751425
references.citation: Cytokine. 1995 Jan;7(1):26-38
references.pmid: 7749064
references.citation: Acta Neurol Scand. 1995 Apr;91(4):276-9
references.pmid: 7542828
references.citation: J Neuroimmunol. 1995 Sep;61(2):205-12
references.pmid: 7593556
references.citation: Cell. 1995 Dec 1;83(5):793-802
references.pmid: 8521496
references.citation: Neurology. 1996 Dec;47(6):1531-4
references.pmid: 8960740
references.citation: Nature. 1997 Feb 20;385(6618):729-33
references.pmid: 9034190
references.citation: Am J Pathol. 1998 Sep;153(3):801-13
references.pmid: 9736029
references.citation: Neurology. 1999 Aug 11;53(3):457-65
references.pmid: 10449104
references.citation: J Exp Med. 2005 Jan 17;201(2):233-40
references.pmid: 15657292
references.citation: Blood. 2005 Feb 15;105(4):1815-22
references.pmid: 15494428
references.citation: Blood. 2005 Apr 1;105(7):2821-7
references.pmid: 15591115
references.citation: Brain. 2005 May;128(Pt 5):988-1002
references.pmid: 15743872
references.citation: Neurology. 2005 Apr 26;64(8):1468-70
references.pmid: 15851749
references.citation: J Immunol. 2006 Jul 1;177(1):566-73
references.pmid: 16785554
references.citation: Blood. 2007 Jan 1;109(1):228-34
references.pmid: 16985180
references.citation: Nat Immunol. 2007 Apr;8(4):345-50
references.pmid: 17375096
references.citation: Annu Rev Immunol. 2007;25:821-52
references.pmid: 17201677
references.citation: J Immunol. 2007 Aug 1;179(3):1449-57
references.pmid: 17641010
references.citation: Nat Med. 2007 Oct;13(10):1173-5
references.pmid: 17828272
references.citation: Stem Cells. 2008 Jan;26(1):212-22
references.pmid: 17932417
references.citation: Blood. 2008 Feb 1;111(3):1327-33
references.pmid: 17951526
references.citation: Eur J Immunol. 2008 Oct;38(10):2636-49
references.pmid: 18958872
references.citation: Nat Med. 2009 Jan;15(1):42-9
references.pmid: 19098906
references.citation: J Neuroimmunol. 2009 Feb 15;207(1-2):83-91
references.pmid: 19174310
references.citation: Exp Hematol. 2009 May;37(5):604-15
references.pmid: 19375651
references.citation: J Immunol. 2009 May 15;182(10):5994-6002
references.pmid: 19414750
references.citation: Eur J Immunol. 2009 Oct;39(10):2840-9
references.pmid: 19637224
references.citation: J Immunol. 2009 Dec 15;183(12):7787-98
references.pmid: 19923445
references.citation: Scand J Immunol. 2010 Apr;71(4):267-74
references.pmid: 20384870
references.citation: J Neurochem. 2010 Sep;114(6):1569-80
references.pmid: 20028455
references.citation: Mol Ther. 2010 Oct;18(10):1857-64
references.pmid: 20664529
references.citation: Eur J Immunol. 2011 Oct;41(10):2840-51
references.pmid: 21710489
references.citation: Stem Cell Res. 2009 Jul;3(1):63-70
references.pmid: 19411199
references.citation: Exp Hematol. 2012 Sep;40(9):761-70
references.pmid: 22634392
references.citation: Arthritis Res Ther. 2012;14(3):R99
references.pmid: 22546542
references.citation: Stem Cells. 2014 Oct;32(10):2799-810
references.pmid: 24906203
references.citation: Cell. 2001 Feb 23;104(4):487-501
references.pmid: 11239407
references.citation: Neurology. 2001 Nov 27;57(10):1885-8
references.pmid: 11723281
references.citation: J Neurosci. 2002 Apr 1;22(7):RC216
references.pmid: 11917000
references.citation: Nat Med. 2002 May;8(5):500-8
references.pmid: 11984595
references.citation: Blood. 2002 May 15;99(10):3838-43
references.pmid: 11986244
references.citation: Blood. 2003 May 1;101(9):3722-9
references.pmid: 12506037
references.citation: J Immunol. 2003 Dec 1;171(11):6173-7
references.pmid: 14634133
references.citation: Transplantation. 1974 Apr;17(4):331-40
references.pmid: 4150881
references.citation: Nature. 1985 Nov 14-20;318(6042):104-5
references.pmid: 2414671
references.citation: Ann Neurol. 1988 Apr;23(4):339-46
references.pmid: 3132891
references.citation: J Exp Med. 1989 Aug 1;170(2):607-12
references.pmid: 2754393
references.citation: Cell. 1990 Apr 20;61(2):351-9
references.pmid: 2158862
references.citation: Proc Natl Acad Sci U S A. 1990 Nov;87(21):8331-5
references.pmid: 2172983
references.citation: J Clin Invest. 1991 Mar;87(3):949-54
references.pmid: 1999503
references.citation: N Engl J Med. 1991 Aug 15;325(7):467-72
references.pmid: 1852181
references.citation: Cytokine. 1990 Nov;2(6):402-6
references.pmid: 2129506
references.citation: Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4845-9
references.pmid: 1317575
references.citation: Eur Cytokine Netw. 1992 Nov-Dec;3(6):523-31
references.pmid: 1296800
references.citation: Nat Immunol. 2005 Nov;6(11):1123-32
references.pmid: 16200070
references.citation: Nat Immunol. 2005 Nov;6(11):1133-41
references.pmid: 16200068
references.citation: Exp Neurol. 2006 Mar;198(1):54-64
references.pmid: 16336965
references.citation: J Immunol. 1993 Aug 1;151(3):1548-61
references.pmid: 8393046
references.citation: J Neuroimmunol. 1995 Feb;56(2):135-41
references.pmid: 7860709
references.citation: Cell Immunol. 2005 Oct;237(2):123-30
references.pmid: 16386239