title: A novel role for IkappaBzeta in the regulation of IFNgamma production.
abstract: IkappaBzeta is a novel member of the IkappaB family of NFkappaB regulators, which modulates NFkappaB activity in the nucleus, rather than controlling its nuclear translocation. IkappaBzeta is specifically induced by IL-1beta and several TLR ligands and positively regulates NFkappaB-mediated transcription of genes such as IL-6 and NGAL as an NFkappaB binding co-factor. We recently reported that the IL-1 family cytokines, IL-1beta and IL-18, strongly synergize with TNFalpha for IFNgamma production in KG-1 cells, whereas the same cytokines alone have minimal effects on IFNgamma production. Given the striking similarities between the IL-1R and IL-18R signaling pathways we hypothesized that a common signaling event or gene product downstream of these receptors is responsible for the observed synergy. We investigated IkappaBzeta protein expression in KG-1 cells upon stimulation with IL-1beta, IL-18 and TNFalpha. Our results demonstrated that IL-18, as well as IL-1beta, induced moderate IkappaBzeta expression in KG-1 cells. However, TNFalpha synergized with IL-1beta and IL-18, whereas by itself it had a minimal effect on IkappaBzeta expression. NFkappaB inhibition resulted in decreased IL-1beta/IL-18/TNFalpha-stimulated IFNgamma release. Moreover, silencing of IkappaBzeta expression led to a specific decrease in IFNgamma production. Overall, our data suggests that IkappaBzeta positively regulates NFkappaB-mediated IFNgamma production in KG-1 cells.
authors.affiliation: The Ohio State University, Davis Heart and Lung Research Institute, Columbus, Ohio, USA.
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Raices
authors.forename: Yashaswini
authors.initials: Y
authors.lastname: Kannan
authors.forename: Vedavathi
authors.initials: V
authors.lastname: Bellamkonda-Athmaram
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Seshadri
authors.forename: Huating
authors.initials: H
authors.lastname: Wang
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wewers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D015153:Blotting, Western; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D020672:I-kappa B Proteins; D007371:Interferon-gamma / Q000096:biosynthesis*; D009687:Nuclear Proteins / Q000502:physiology*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020672:I-kappa B Proteins; C417234:NFKBIZ protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D007371:Interferon-gamma
references.citation: Curr Top Microbiol Immunol. 2007;316:97-117
references.pmid: 17969445
references.citation: J Vet Med Sci. 2007 Mar;69(3):279-84
references.pmid: 17409644
references.citation: J Immunol. 2002 Feb 1;168(3):1146-53
references.pmid: 11801649
references.citation: J Immunol. 2001 Mar 1;166(5):3075-82
references.pmid: 11207258
references.citation: J Immunol. 2003 Apr 15;170(8):4226-36
references.pmid: 12682256
references.citation: J Biol Chem. 2001 Jul 20;276(29):27657-62
references.pmid: 11356851
references.citation: J Biol Chem. 2002 Mar 29;277(13):10998-1003
references.pmid: 11790772
references.citation: J Immunol. 1998 Apr 15;160(8):3642-7
references.pmid: 9558063
references.citation: Biochem Biophys Res Commun. 1998 Mar 6;244(1):183-6
references.pmid: 9514903
references.citation: Mol Cell. 2004 Oct 8;16(1):35-45
references.pmid: 15469820
references.citation: Sci STKE. 2003 Feb 25;2003(171):re3
references.pmid: 12606705
references.citation: Vitam Horm. 2006;74:301-16
references.pmid: 17027520
references.citation: Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2489-93
references.pmid: 1532257
references.citation: J Leukoc Biol. 2003 Feb;73(2):213-24
references.pmid: 12554798
references.citation: J Immunol. 2005 Mar 1;174(5):2796-804
references.pmid: 15728489
references.citation: Cytokine. 2008 Nov;44(2):234-41
references.pmid: 18805021
references.citation: J Immunol. 2003 Jun 1;170(11):5571-7
references.pmid: 12759435
references.citation: J Biol Chem. 1997 Oct 10;272(41):25737-42
references.pmid: 9325300
references.citation: Cytokine. 2002 Nov 7;20(3):91-106
references.pmid: 12453467
references.citation: Immunity. 1999 Jan;10(1):127-36
references.pmid: 10023777
references.citation: J Immunol. 1990 Jul 1;145(1):161-6
references.pmid: 2358670
references.citation: Mol Immunol. 2004 Feb;40(12):861-8
references.pmid: 14698224
references.citation: J Gen Virol. 2004 May;85(Pt 5):1291-1299
references.pmid: 15105546
references.citation: EMBO J. 1993 Oct;12(10):3893-901
references.pmid: 8404857
references.citation: Leuk Res. 2003 Sep;27(9):813-22
references.pmid: 12804640
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3948-53
references.pmid: 9108085
references.citation: J Biol Chem. 1997 Dec 26;272(52):33132-9
references.pmid: 9407099
references.citation: Genes Dev. 1992 Dec;6(12A):2352-63
references.pmid: 1459457
references.citation: FEBS Lett. 2000 Nov 17;485(1):53-6
references.pmid: 11086164
references.citation: J Exp Med. 1998 Oct 19;188(8):1485-92
references.pmid: 9782125
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13723-8
references.pmid: 12381835
references.citation: Leukemia. 2000 Jun;14(6):1052-9
references.pmid: 10865972
references.citation: J Biol Chem. 1994 Jul 22;269(29):19021-7
references.pmid: 8034659
references.citation: J Immunol. 2006 Jun 1;176(11):6647-55
references.pmid: 16709823
references.citation: Nature. 1992 Sep 24;359(6393):339-42
references.pmid: 1406939
references.citation: Genes Dev. 1993 Jul;7(7B):1354-63
references.pmid: 8330739
references.citation: Blood. 2006 Feb 15;107(4):1468-75
references.pmid: 16249390
references.citation: Immunogenetics. 2001 Oct;53(8):649-55
references.pmid: 11797098
references.citation: J Immunol. 2003 Jan 1;170(1):575-80
references.pmid: 12496445
references.citation: J Biol Chem. 1997 Nov 28;272(48):30412-20
references.pmid: 9374532
references.citation: Cell. 1993 Mar 12;72(5):729-39
references.pmid: 8453667
references.citation: J Pathol. 2008 Jan;214(2):149-60
references.pmid: 18161752
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13962-6
references.pmid: 10570181
references.citation: J Immunol. 2003 Jun 1;170(11):5583-9
references.pmid: 12759437
references.citation: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11537-42
references.pmid: 10500212
references.citation: J Immunol. 2000 Jan 1;164(1):64-71
references.pmid: 10604994
references.citation: J Leukoc Biol. 1995 Oct;58(4):373-81
references.pmid: 7561512
references.citation: Nature. 2004 Jul 8;430(6996):218-22
references.pmid: 15241416
references.citation: Curr Opin Immunol. 1998 Jun;10(3):259-64
references.pmid: 9638361
references.citation: J Immunol. 2003 Dec 15;171(12):6630-9
references.pmid: 14662866
references.citation: J Biol Chem. 2006 May 5;281(18):12645-54
references.pmid: 16513645
references.citation: Nature. 2000 Aug 17;406(6797):782-7
references.pmid: 10963608
references.citation: J Biol Chem. 2004 Nov 26;279(48):49995-50003
references.pmid: 15465827
references.citation: J Immunol. 1989 Jun 1;142(11):3862-7
references.pmid: 2523936
references.citation: J Mol Biol. 2008 May 23;379(1):122-35
references.pmid: 18436238
references.citation: Biochem J. 2007 Aug 1;405(3):605-15
references.pmid: 17447895
references.citation: Arch Histol Cytol. 2003 Mar;66(1):53-62
references.pmid: 12703554
references.citation: Mol Cell Biol. 1996 Apr;16(4):1342-8
references.pmid: 8657107
references.citation: Nature. 1992 Aug 13;358(6387):597-9
references.pmid: 1501714
references.citation: J Endotoxin Res. 2003;9(3):187-91
references.pmid: 12831461
references.citation: Gene. 2004 Nov 10;342(1):137-43
references.pmid: 15527973
references.citation: Immunity. 1997 Oct;7(4):571-81
references.pmid: 9354477
references.citation: Int Immunol. 2000 Feb;12(2):151-60
references.pmid: 10653850
references.citation: J Immunol. 1998 Oct 1;161(7):3400-7
references.pmid: 9759857
references.citation: J Invest Dermatol. 2002 Feb;118(2):275-81
references.pmid: 11841544
references.citation: J Immunol. 2006 May 1;176(9):5559-66
references.pmid: 16622025
references.citation: Mol Cell Biol. 1994 Jun;14(6):3915-26
references.pmid: 8196632
references.citation: Methods. 1999 Sep;19(1):121-32
references.pmid: 10525448
references.citation: Mol Cell Biol. 1993 Jun;13(6):3557-66
references.pmid: 8497270
references.citation: J Biol Chem. 2008 May 2;283(18):12468-77
references.pmid: 18319258
references.citation: Nat Rev Immunol. 2004 Jul;4(7):499-511
references.pmid: 15229469
references.citation: J Biol Chem. 2008 May 30;283(22):15309-18
references.pmid: 18362142
references.citation: J Interferon Cytokine Res. 1996 Aug;16(8):563-8
references.pmid: 8877725
references.citation: J Immunol. 2001 Jul 15;167(2):957-65
references.pmid: 11441104
references.citation: J Biol Chem. 2005 Jan 14;280(2):1678-87
references.pmid: 15522867
references.citation: J Biol Chem. 2001 Apr 20;276(16):12485-8
references.pmid: 11278262
references.citation: J Biol Chem. 1990 Oct 5;265(28):17238-45
references.pmid: 1698773
references.citation: J Immunol. 1999 May 1;162(9):5063-9
references.pmid: 10227974
references.citation: J Immunol. 2005 Apr 15;174(8):4870-9
references.pmid: 15814714
references.citation: Nature. 2004 Dec 16;432(7019):917-21
references.pmid: 15531878
references.citation: J Immunol. 2001 Nov 15;167(10):5913-20
references.pmid: 11698468
references.citation: J Biol Chem. 2005 Mar 4;280(9):7444-51
references.pmid: 15618216
references.citation: Nat Rev Immunol. 2002 Oct;2(10):725-34
references.pmid: 12360211
references.citation: Biochem Biophys Res Commun. 1997 May 19;234(2):454-7
references.pmid: 9177292
references.citation: J Vet Med Sci. 2002 May;64(5):419-22
references.pmid: 12069074