title: IkappaBzeta regulates T(H)17 development by cooperating with ROR nuclear receptors.
abstract: Interleukin (IL)-17-producing helper T (T(H)17) cells are a distinct T-cell subset characterized by its pathological role in autoimmune diseases. IL-6 and transforming growth factor-beta (TGF-beta) induce T(H)17 development, in which the orphan nuclear receptors, RORgammat and RORalpha, have an indispensable role. However, in the absence of IL-6 and TGF-beta, the ectopic expression of RORgammat or RORalpha leads to only a modest IL-17 production. Here we identify a nuclear IkappaB family member, IkappaBzeta (encoded by the Nfkbiz gene), as a transcription factor required for T(H)17 development in mice. The ectopic expression of IkappaBzeta in naive CD4(+) T cells together with RORgammat or RORalpha potently induces T(H)17 development, even in the absence of IL-6 and TGF-beta. Notably, Nfkbiz(-/-) mice have a defect in T(H)17 development and a resistance to experimental autoimmune encephalomyelitis (EAE). The T-cell-intrinsic function of IkappaBzeta was clearly demonstrated by the resistance to EAE of the Rag2(-/-) mice into which Nfkbiz(-/-) CD4(+) T cells were transferred. In cooperation with RORgammat and RORalpha, IkappaBzeta enhances Il17a expression by binding directly to the regulatory region of the Il17a gene. This study provides evidence for the transcriptional mechanisms underlying T(H)17 development and points to a molecular basis for a novel therapeutic strategy against autoimmune disease.
authors.affiliation: Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Okamoto
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwai
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Oh-Hora
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Aoki
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ohya
authors.forename: Anton M
authors.initials: AM
authors.lastname: Jetten
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Muta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism; D005786:Gene Expression Regulation; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics / Q000378:metabolism*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020381:Interleukin-17; D052002:NF-kappa B p50 Subunit; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3
references.citation: Adv Dev Biol. 2006;16:313-355
references.pmid: 18418469
references.citation: Vitam Horm. 2006;74:301-16
references.pmid: 17027520
references.citation: Nat Immunol. 2008 Nov;9(11):1297-306
references.pmid: 18849990
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10132-7
references.pmid: 10963675
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W217-21
references.pmid: 15215384
references.citation: J Immunol. 1998 Nov 1;161(9):4652-60
references.pmid: 9794394
references.citation: Nat Immunol. 2007 Sep;8(9):958-66
references.pmid: 17676043
references.citation: Nat Immunol. 2008 Jun;9(6):641-9
references.pmid: 18454151
references.citation: Biochem J. 2007 Aug 1;405(3):605-15
references.pmid: 17447895
references.citation: Cell. 1995 Jan 27;80(2):321-30
references.pmid: 7834752
references.citation: J Biol Chem. 2005 Jan 14;280(2):1678-87
references.pmid: 15522867
references.citation: J Biol Chem. 2007 Mar 2;282(9):5969-72
references.pmid: 17218320
references.citation: J Biol Chem. 2005 Mar 4;280(9):7444-51
references.pmid: 15618216
references.citation: Cell. 2006 Sep 22;126(6):1121-33
references.pmid: 16990136
references.citation: Immunity. 2006 Feb;24(2):179-89
references.pmid: 16473830
references.citation: Nature. 1996 Feb 22;379(6567):736-9
references.pmid: 8602221
references.citation: Nat Rev Immunol. 2008 May;8(5):337-48
references.pmid: 18408735
references.citation: Microbes Infect. 2009 Apr;11(5):599-611
references.pmid: 19379825
references.citation: Proc Natl Acad Sci U S A. 2006 May 23;103(21):8137-42
references.pmid: 16698929
references.citation: Nature. 2008 May 1;453(7191):65-71
references.pmid: 18362915
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20846-51
references.pmid: 19088203
references.citation: Science. 2008 Feb 1;319(5863):624-7
references.pmid: 18239127
references.citation: J Infect Chemother. 2008 Aug;14(4):265-9
references.pmid: 18709529
references.citation: Immunity. 2002 Sep;17(3):375-87
references.pmid: 12354389
references.citation: Nature. 2004 Jul 8;430(6996):218-22
references.pmid: 15241416
references.citation: Immunity. 2008 Jan;28(1):29-39
references.pmid: 18164222
references.citation: Nat Med. 2005 Aug;11(8):880-5
references.pmid: 16041384
references.citation: Immunity. 1998 Jul;9(1):143-50
references.pmid: 9697844
references.citation: Nature. 2009 Jul 16;460(7253):405-9
references.pmid: 19578362
references.citation: Annu Rev Immunol. 2009;27:485-517
references.pmid: 19132915
references.citation: Nature. 2008 May 1;453(7191):106-9
references.pmid: 18362914
references.citation: Cell. 2008 Mar 7;132(5):794-806
references.pmid: 18329366
references.citation: J Biol Chem. 2001 Jul 20;276(29):27657-62
references.pmid: 11356851
references.citation: Exp Hematol. 2003 Nov;31(11):1007-14
references.pmid: 14585362
references.citation: J Biol Chem. 2004 Dec 31;279(53):55493-8
references.pmid: 15491998