title: Tissue inhibitor of metalloproteinase 1 is preferentially expressed in Th1 and Th17 T-helper cell subsets and is a direct STAT target gene.
abstract: CD4(+) T helper (Th) cells differentiate into distinct effector subsets that are critical for host defense, but are also implicated in the pathogenesis of autoimmune disorders. Thelper17 (Th17) cells in particular are emerging as important drivers of multiple diseases including psoriasis, spondyloarthropathy and multiple sclerosis. To gain insight into the function of Th17 cells, we performed transcriptional profiling in hopes of elucidating products not previously recognized as being functionally relevant in these T cells. Herein, we demonstrate that tissue inhibitor of metalloproteinase 1 (TIMP1), a secreted protein with pleiotropic effects on cellular growth, survival and integrity of the extracellular matrix, is preferentially produced by Th17 and Th1 cells. We further show that Th1 and Th17 cell TIMP1 regulation follows separate mechanisms with a requirement for STAT4 in the former and STAT3 in the latter. Finally, we demonstrate that when restricted to T cells, expression of TIMP1 promotes neuropathology in experimental allergic encephalomyelitis.
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Adewole
authors.initials: A
authors.lastname: Adamson
authors.forename: Kamran
authors.initials: K
authors.lastname: Ghoreschi
authors.forename: Matthew
authors.initials: M
authors.lastname: Rittler
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Sun
authors.forename: Golnaz
authors.initials: G
authors.lastname: Vahedi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kanno
authors.forename: William G
authors.initials: WG
authors.lastname: Stetler-Stevenson
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
authors.forename: Arian
authors.initials: A
authors.lastname: Laurence
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000276:immunology*; D014158:Transcription, Genetic
chemical_list: D016207:Cytokines; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; C494087:Stat3 protein, mouse; C494091:Stat4 protein, mouse; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1
references.citation: J Exp Med. 2003 Dec 15;198(12):1951-7
references.pmid: 14662908
references.citation: Clin Cancer Res. 2002 Jan;8(1):156-64
references.pmid: 11801553
references.citation: Am J Pathol. 2012 Jan;180(1):12-6
references.pmid: 22033229
references.citation: J Immunol. 2004 Oct 15;173(8):5209-18
references.pmid: 15470066
references.citation: Nature. 2008 Apr 10;452(7188):773-6
references.pmid: 18337720
references.citation: Cell. 2012 Nov 21;151(5):981-93
references.pmid: 23178119
references.citation: J Biol Chem. 2007 Nov 30;282(48):34605-10
references.pmid: 17884812
references.citation: Arthritis Rheum. 2007 Sep;56(9):2936-46
references.pmid: 17763419
references.citation: World J Gastroenterol. 2007 Jun 7;13(21):2960-6
references.pmid: 17589947
references.citation: Nat Immunol. 2011 Mar;12(3):247-54
references.pmid: 21278738
references.citation: Cytokine. 2011 Oct;56(1):112-5
references.pmid: 21813287
references.citation: Immunity. 2006 Feb;24(2):179-89
references.pmid: 16473830
references.citation: N Engl J Med. 2009 Aug 27;361(9):888-98
references.pmid: 19710487
references.citation: N Engl J Med. 2009 Jul 30;361(5):496-509
references.pmid: 19641206
references.citation: Nat Rev Immunol. 2008 May;8(5):337-48
references.pmid: 18408735
references.citation: Int J Cancer. 1998 Jan 5;75(1):81-7
references.pmid: 9426694
references.citation: Neuro Oncol. 2011 Jan;13(1):99-108
references.pmid: 21163810
references.citation: Arthritis Rheum. 1996 May;39(5):844-54
references.pmid: 8639182
references.citation: J Neuroimmunol. 2007 Feb;183(1-2):96-103
references.pmid: 17240458
references.citation: Proc Natl Acad Sci U S A. 2006 May 23;103(21):8137-42
references.pmid: 16698929
references.citation: Immunity. 2010 May 28;32(5):616-27
references.pmid: 20471290
references.citation: Annu Rev Immunol. 2003;21:713-58
references.pmid: 12500979
references.citation: Am J Pathol. 2010 Aug;177(2):840-53
references.pmid: 20558576
references.citation: Genes Immun. 2010 Apr;11(3):264-8
references.pmid: 20200543
references.citation: Nat Rev Immunol. 2009 Dec;9(12):883-9
references.pmid: 19935807
references.citation: J Autoimmun. 2001 Jun;16(4):463-70
references.pmid: 11437495
references.citation: EMBO J. 2003 Aug 15;22(16):4237-48
references.pmid: 12912921
references.citation: J Rheumatol. 2009 Oct;36(10):2149-57
references.pmid: 19723899
references.citation: Curr Protoc Cell Biol. 2008 Sep;Chapter 10:Unit 10.8
references.pmid: 18819088
references.citation: N Engl J Med. 2011 Oct 27;365(17):1612-23
references.pmid: 22029983
references.citation: J Exp Med. 2006 Apr 17;203(4):1007-19
references.pmid: 16585265
references.citation: Nature. 2003 Feb 13;421(6924):744-8
references.pmid: 12610626
references.citation: J Exp Med. 1994 Nov 1;180(5):1961-6
references.pmid: 7525845
references.citation: J Exp Med. 2006 Jul 10;203(7):1685-91
references.pmid: 16818675
references.citation: Immunity. 2002 Jul;17(1):63-72
references.pmid: 12150892
references.citation: Scand J Immunol. 2009 Jul;70(1):68-74
references.pmid: 19522770
references.citation: J Exp Med. 2003 May 5;197(9):1073-81
references.pmid: 12732654
references.citation: Immunity. 2010 Jun 25;32(6):840-51
references.pmid: 20620946
references.citation: Sci Signal. 2008 Jul 08;1(27):re6
references.pmid: 18612141
references.citation: Annu Rev Immunol. 1989;7:145-73
references.pmid: 2523712
references.citation: Immunity. 2009 Apr 17;30(4):576-87
references.pmid: 19362022
references.citation: Immunity. 2012 Apr 20;36(4):542-50
references.pmid: 22520847
references.citation: Exp Neurol. 2002 Nov;178(1):13-20
references.pmid: 12460604
references.citation: Arthritis Rheum. 1993 Mar;36(3):372-9
references.pmid: 8452582
references.citation: Annu Rev Immunol. 2010;28:445-89
references.pmid: 20192806
references.citation: Nature. 2010 Oct 21;467(7318):967-71
references.pmid: 20962846
references.citation: J Virol. 2005 Apr;79(8):4764-73
references.pmid: 15795262
references.citation: Ann Rheum Dis. 2001 Sep;60(9):846-51
references.pmid: 11502611