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T helper 17 (Th17) cells produce interleukin-17 (IL-17) cytokines and drive inflammatory responses in autoimmune diseases such as multiple sclerosis. The differentiation of Th17 cells is dependent on the retinoic acid receptor-related orphan nuclear receptor RORγt. Here, we identify REV-ERBα (encoded by Nr1d1 ), a member of the nuclear hormone receptor family, as a transcriptional repressor that antagonizes RORγt function in Th17 cells. REV-ERBα binds to ROR response elements (RORE) in Th17 cells and inhibits the expression of RORγt-dependent genes including Il17a and Il17f Furthermore, elevated REV-ERBα expression or treatment with a synthetic REV-ERB agonist significantly delays the onset and impedes the progression of experimental autoimmune encephalomyelitis (EAE). These results suggest that modulating REV-ERBα activity may be used to manipulate Th17 cells in autoimmune diseases.

Competing Interests: The authors declare no conflict of interest.

Titel:	The nuclear receptor REV-ERBα modulates Th17 cell-mediated autoimmune disease.
Autor/in / Beteiligte Person:	Chang, C ; Loo, CS ; Zhao, X ; Solt, LA ; Liang, Y ; Bapat, SP ; Cho, H ; Kamenecka, TM ; Leblanc, M ; Atkins, AR ; Yu, RT ; Downes, M ; Burris, TP ; Evans, RM ; Zheng, Y
Link:	Full Text Finder (Volltext)
Zeitschrift:	Proceedings of the National Academy of Sciences of the United States of America, Jg. 116 (2019-09-10), Heft 37, S. 18528-18536
Veröffentlichung:	Washington, DC : National Academy of Sciences, 2019
Medientyp:	academicJournal
ISSN:	1091-6490 (electronic)
DOI:	10.1073/pnas.1907563116
Schlagwort:	Amino Acid Motifs genetics Amino Acid Motifs immunology Animals Cell Differentiation genetics Cell Differentiation immunology Encephalomyelitis, Autoimmune, Experimental drug therapy Encephalomyelitis, Autoimmune, Experimental genetics Gene Expression Regulation drug effects Gene Expression Regulation immunology Genetic Loci HEK293 Cells Humans Interleukin-17 genetics Interleukin-17 immunology Interleukin-17 metabolism Mice Mice, Transgenic Multiple Sclerosis drug therapy Multiple Sclerosis genetics Nuclear Receptor Subfamily 1, Group D, Member 1 agonists Nuclear Receptor Subfamily 1, Group D, Member 1 immunology Nuclear Receptor Subfamily 1, Group F, Member 3 immunology Pyrrolidines pharmacology Pyrrolidines therapeutic use RNA-Seq Response Elements genetics Th17 Cells metabolism Thiophenes pharmacology Thiophenes therapeutic use Encephalomyelitis, Autoimmune, Experimental immunology Multiple Sclerosis immunology Nuclear Receptor Subfamily 1, Group D, Member 1 metabolism Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism Th17 Cells immunology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Proc Natl Acad Sci U S A] 2019 Sep 10; Vol. 116 (37), pp. 18528-18536. <i>Date of Electronic Publication: </i>2019 Aug 27. MeSH Terms: Encephalomyelitis, Autoimmune, Experimental / immunology ; Multiple Sclerosis / immunology ; Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism ; Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism ; Th17 Cells / *immunology ; Amino Acid Motifs / genetics ; Amino Acid Motifs / immunology ; Animals ; Cell Differentiation / genetics ; Cell Differentiation / immunology ; Encephalomyelitis, Autoimmune, Experimental / drug therapy ; Encephalomyelitis, Autoimmune, Experimental / genetics ; Gene Expression Regulation / drug effects ; Gene Expression Regulation / immunology ; Genetic Loci ; HEK293 Cells ; Humans ; Interleukin-17 / genetics ; Interleukin-17 / immunology ; Interleukin-17 / metabolism ; Mice ; Mice, Transgenic ; Multiple Sclerosis / drug therapy ; Multiple Sclerosis / genetics ; Nuclear Receptor Subfamily 1, Group D, Member 1 / agonists ; Nuclear Receptor Subfamily 1, Group D, Member 1 / immunology ; Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology ; Pyrrolidines / pharmacology ; Pyrrolidines / therapeutic use ; RNA-Seq ; Response Elements / genetics ; Th17 Cells / metabolism ; Thiophenes / pharmacology ; Thiophenes / therapeutic use References: Nature. 2002 Aug 1;418(6897):534-9. (PMID: 12152080) ; Bioinformatics. 2003 Jan 22;19(2):295-6. (PMID: 12538257) ; J Exp Med. 2003 May 5;197(9):1073-81. (PMID: 12732654) ; Neuron. 2004 Aug 19;43(4):527-37. (PMID: 15312651) ; Science. 2006 Feb 17;311(5763):1002-5. (PMID: 16484495) ; Cell. 2006 Sep 22;126(6):1121-33. (PMID: 16990136) ; Annu Rev Immunol. 2007;25:821-52. (PMID: 17201677) ; PLoS Biol. 2007 Feb;5(2):e34. (PMID: 17298173) ; J Mol Biol. 2007 Oct 26;373(3):735-44. (PMID: 17870090) ; Science. 2007 Dec 14;318(5857):1786-9. (PMID: 18006707) ; Nat Struct Mol Biol. 2007 Dec;14(12):1207-13. (PMID: 18037887) ; Immunity. 2008 Jan;28(1):29-39. (PMID: 18164222) ; Nat Immunol. 2008 Oct;9(10):1091-4. (PMID: 18800157) ; Nat Immunol. 2008 Nov;9(11):1297-306. (PMID: 18849990) ; Nucleic Acids Res. 2009 Jan;37(1):1-13. (PMID: 19033363) ; Nat Protoc. 2009;4(1):44-57. (PMID: 19131956) ; Annu Rev Immunol. 2009;27:485-517. (PMID: 19132915) ; Nucl Recept Signal. 2009;7:e003. (PMID: 19381306) ; Nucl Recept Signal. 2010 Apr 16;8:e001. (PMID: 20414452) ; Nature. 2011 Apr 28;472(7344):486-90. (PMID: 21441909) ; Nature. 2011 Apr 28;472(7344):491-4. (PMID: 21499262) ; Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):582-7. (PMID: 22184247) ; Immunity. 2012 Jan 27;36(1):23-31. (PMID: 22244845) ; Nature. 2012 Mar 29;485(7396):62-8. (PMID: 22460951) ; Nature. 2012 Mar 29;485(7396):123-7. (PMID: 22460952) ; Cell. 2012 Oct 12;151(2):289-303. (PMID: 23021777) ; Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886) ; Nat Biotechnol. 2013 Jan;31(1):46-53. (PMID: 23222703) ; Nat Med. 2013 Aug;19(8):1039-46. (PMID: 23852339) ; Science. 2013 Nov 8;342(6159):727-30. (PMID: 24202171) ; Immunity. 2014 Apr 17;40(4):477-89. (PMID: 24745332) ; Science. 2015 Jun 26;348(6242):1488-92. (PMID: 26044300) ; Cell. 2015 Sep 10;162(6):1338-52. (PMID: 26359987) ; Nat Commun. 2015 Dec 07;6:8833. (PMID: 26640126) ; Cell. 2016 Jun 16;165(7):1644-1657. (PMID: 27238018) ; Expert Opin Ther Pat. 2017 Jan;27(1):1-8. (PMID: 27852111) ; Cell Rep. 2016 Dec 20;17(12):3206-3218. (PMID: 28009290) ; Nature. 2018 Jan 18;553(7688):351-355. (PMID: 29320480) ; Cell Rep. 2018 Dec 26;25(13):3733-3749.e8. (PMID: 30590045) ; Proc Natl Acad Sci U S A. 2019 Jun 18;116(25):12147-12152. (PMID: 31127047) ; J Virol. 1996 Aug;70(8):5701-5. (PMID: 8764092) Grant Information: R01 HL105278 United States HL NHLBI NIH HHS; T32 GM007198 United States GM NIGMS NIH HHS; P30 CA008748 United States CA NCI NIH HHS; S10 OD023689 United States OD NIH HHS; R01 AI107027 United States AI NIAID NIH HHS; United States HHMI Howard Hughes Medical Institute; P42 ES010337 United States ES NIEHS NIH HHS; R01 AI116885 United States AI NIAID NIH HHS; P30 CA014195 United States CA NCI NIH HHS Contributed Indexing: Keywords: autoimmunity; nuclear receptors; transcriptional repressor Substance Nomenclature: 0 (Il17a protein, mouse) ; 0 (Il17f protein, mouse) ; 0 (Interleukin-17) ; 0 (Nr1d1 protein, mouse) ; 0 (Nuclear Receptor Subfamily 1, Group D, Member 1) ; 0 (Nuclear Receptor Subfamily 1, Group F, Member 3) ; 0 (Pyrrolidines) ; 0 (Rorc protein, mouse) ; 0 (SR9009) ; 0 (Thiophenes) Entry Date(s): Date Created: 20190829 Date Completed: 20200406 Latest Revision: 20201107 Update Code: 20240513 PubMed Central ID: PMC6744854

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The nuclear receptor REV-ERBα modulates Th17 cell-mediated autoimmune disease.