The feedback phase of type I interferon induction in dendritic cells requires interferon regulatory factor 8.
Dendritic cells (DCs) produce type I interferons (IFNs) in greater amounts than other cells, but the mechanisms remain elusive. Here we studied the role of a transcription factor, IRF8, in DC induction of type I IFNs. Upon newcastle disease virus (NDV) infection, bone marrow-derived plasmacytoid and conventional DCs induced IFN transcripts, exhibiting two-phase kinetics. The second, amplifying phase represented an IFN feedback response that accounted for much of IFN protein production. Induction of second phase transcription required IRF8. Mouse cytomegalovirus (MCMV) and Toll-like receptor-mediated IFN induction in DCs also required IRF8. Chromatin immunoprecipitation analysis showed that IRF7, IRF8, and RNA polymerase II were recruited to the IFN promoters upon stimulation. Moreover, sustained RNA polymerase II recruitment to the promoters critically depended on IRF8. Together, these data indicate that IRF8 magnifies the second phase of IFN transcription in DCs by prolonging binding of basic transcription machinery to the IFN promoters, thereby playing a role in innate immunity.
Tailor
Prafullakumar
P
Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Tamura
Tomohiko
T
Kong
Hee Jeong
HJ
Kubota
Toru
T
Kubota
Mayumi
M
Borghi
Paola
P
Gabriele
Lucia
L
Ozato
Keiko
K
D000818:Animals; D047369:Chromatin Immunoprecipitation; D003713:Dendritic Cells / Q000276:immunology*; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000276:immunology; D005786:Gene Expression Regulation; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D007370:Interferon Type I / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D012319:RNA Polymerase II; D000099185:Interferon Regulatory Factor-8; C494235:Irf7 protein, mouse
Recent Prog Horm Res. 1996;51:391-403; discussion 403-4
8701087
Genes Dev. 2004 Oct 15;18(20):2437-68
15489290
EMBO J. 1998 Nov 16;17(22):6660-9
9822609
Science. 1999 Jun 11;284(5421):1835-7
10364556
Cold Spring Harb Symp Quant Biol. 1998;63:609-20
10384326
Immunol Rev. 2004 Dec;202:8-32
15546383
FEBS Lett. 2005 Feb 7;579(4):909-15
15680973
J Immunol. 2005 Mar 1;174(5):2573-81
15728463
Nature. 2005 Apr 7;434(7034):772-7
15800576
Nature. 2005 Apr 21;434(7036):1035-40
15815647
Nat Rev Immunol. 2005 May;5(5):375-86
15864272
J Exp Med. 2005 May 2;201(9):1435-46
15851485
Immunity. 2005 Jul;23(1):19-28
16039576
J Exp Med. 2005 Aug 15;202(4):461-5
16103406
J Immunol. 2005 Sep 1;175(5):2851-8
16116171
Blood. 2005 Sep 15;106(6):1938-47
15947094
Nat Immunol. 2005 Oct;6(10):981-8
16127453
Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14368-73
16183743
J Interferon Cytokine Res. 2005 Dec;25(12):770-9
16375605
Nat Immunol. 2006 Feb;7(2):131-7
16424890
Cell Res. 2006 Feb;16(2):134-40
16474425
J Biol Chem. 2006 Feb 24;281(8):4856-66
16380379
Mol Cell Biol. 2006 Sep;26(17):6311-32
16914719
Nat Rev Immunol. 2006 Sep;6(9):644-58
16932750
Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18302-7
17105807
J Immunol. 2007 Jul 1;179(1):26-30
17579016
Cell. 2000 Nov 10;103(4):667-78
11106736
Immunity. 2000 Oct;13(4):539-48
11070172
Immunity. 2001 Jun;14(6):661-4
11420036
Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12426-31
11606780
Nat Immunol. 2001 Dec;2(12):1144-50
11713464
J Interferon Cytokine Res. 2002 Jan;22(1):145-52
11846985
J Interferon Cytokine Res. 2002 Jan;22(1):153-60
11846986
J Exp Med. 2002 Apr 1;195(7):953-8
11927638
Genes Dev. 2002 Sep 1;16(17):2219-24
12208844
Mol Cell Biol. 2002 Nov;22(21):7439-48
12370291
Biochimie. 2002 Jul;84(7):643-54
12453636
J Exp Med. 2002 Dec 2;196(11):1415-25
12461077
Blood. 2003 Jan 1;101(1):305-10
12393690
Blood. 2003 Feb 1;101(3):961-9
12393459
J Immunol. 2003 Feb 1;170(3):1131-5
12538667
Mol Cell. 2003 Mar;11(3):695-707
12667452
J Immunol. 2003 May 1;170(9):4465-74
12707322
J Biol Chem. 2003 May 2;278(18):15495-504
12604599
Science. 2003 May 16;300(5622):1148-51
12702806
Nature. 2003 Jul 17;424(6946):324-8
12819664
Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):233-8
14679297
Immunity. 2004 May;20(5):539-50
15142523
J Immunol. 2004 Aug 1;173(3):1535-48
15265881
J Biol Chem. 1997 Apr 11;272(15):9785-92
9092512