title: A critical role for MAPK signalling pathways in the transcriptional regulation of toll like receptors.
abstract: Toll-like Receptors (TLR) are phylogenetically conserved transmembrane proteins responsible for detection of pathogens and activation of immune responses in diverse animal species. The stimulation of TLR by pathogen-derived molecules leads to the production of pro-inflammatory mediators including cytokines and nitric oxide. Although TLR-induced events are critical for immune induction, uncontrolled inflammation can be life threatening and regulation is a critical feature of TLR biology. We used an avian macrophage cell line (HD11) to determine the relationship between TLR agonist-induced activation of inflammatory responses and the transcriptional regulation of TLR. Exposure of macrophages to specific TLR agonists induced upregulation of cytokine and nitric oxide pathways that were inhibited by blocking various components of the TLR signalling pathways. TLR activation also led to changes in the levels of mRNA encoding the TLR responsible for recognising the inducing agonist (cognate regulation) and cross-regulation of other TLR (non-cognate regulation). Interestingly, in most cases, regulation of TLR mRNA was independent of NFκB activity but dependent on one or more of the MAPK pathway components. Moreover, the relative importance of ERK, JNK and p38 was dependent upon both the stimulating agonist and the target TLR. These results provide a framework for understanding the complex pathways involved in transcriptional regulation of TLR, immune induction and inflammation. Manipulation of these pathways during vaccination or management of acute inflammatory disease may lead to improved clinical outcome or enhanced vaccine efficacy.
authors: Institute for Animal Health, Compton, Berkshire, United Kingdom.
authors: Marylene Y
authors: MY
authors: Peroval
authors: Amy C
authors: AC
authors: Boyd
authors: John R
authors: JR
authors: Young
authors: Adrian L
authors: AL
authors: Smith
mesh_terms: D000818:Animals; D001717:Birds; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D009569:Nitric Oxide; D048051:p38 Mitogen-Activated Protein Kinases
references: Exp Lung Res. 2003 Sep;29(6):401-12
references: 12888452
references: Dev Comp Immunol. 2008;32(4):435-44
references: 17870162
references: J Immunol. 2007 Jun 1;178(11):7110-9
references: 17513760
references: J Immunol. 2006 Jun 15;176(12):7361-70
references: 16751380
references: Cell Death Differ. 2006 May;13(5):816-25
references: 16410796
references: Am J Physiol Cell Physiol. 2003 Aug;285(2):C399-408
references: 12686512
references: Nature. 2004 Mar 18;428(6980):341-5
references: 15029200
references: Vet Immunol Immunopathol. 2002 Jan 15;84(3-4):191-207
references: 11777534
references: Ann N Y Acad Sci. 2002 Jun;968:256-70
references: 12119281
references: J Biol Chem. 2002 Aug 30;277(35):32124-32
references: 12052830
references: Nat Immunol. 2009 Jun;10(6):587-94
references: 19430477
references: Curr Med Chem. 2006;13(21):2487-502
references: 17017906
references: BMC Immunol. 2008 Nov 24;9:69
references: 19025640
references: Cell. 1979 Oct;18(2):375-90
references: 227607
references: J Immunol. 2004 Dec 15;173(12):7548-55
references: 15585882
references: Mamm Genome. 2011 Feb;22(1-2):130-8
references: 21052677
references: J Infect Dis. 2006 Mar 15;193(6):849-59
references: 16479520
references: Dev Comp Immunol. 2009 Sep;33(9):967-73
references: 19539094
references: Clin Immunol. 2009 Jan;130(1):7-15
references: 18964303
references: Arch Biochem Biophys. 2010 Mar 15;495(2):144-51
references: 20064484
references: J Immunol. 2000 Apr 1;164(7):3476-9
references: 10725699
references: Cell Signal. 2008 Sep;20(9):1592-607
references: 18423978
references: Biochem Biophys Res Commun. 2009 Oct 30;388(4):621-5
references: 19686699
references: Mol Pharmacol. 2006 May;69(5):1717-24
references: 16474002
references: Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4968-73
references: 21383168
references: J Biol Chem. 2001 Dec 14;276(50):47143-9
references: 11590137
references: Biochem Soc Trans. 2007 Dec;35(Pt 6):1504-7
references: 18031254
references: J Biol Chem. 1995 Nov 17;270(46):27489-94
references: 7499206
references: Curr Drug Targets Inflamm Allergy. 2004 Sep;3(3):291-7
references: 15379597
references: J Immunol. 2008 Sep 15;181(6):4354-62
references: 18768894
references: Nature. 1999 Oct 21;401(6755):811-5
references: 10548109
references: EMBO J. 2000 Jul 17;19(14):3630-8
references: 10899117
references: Immunity. 2006 May;24(5):563-74
references: 16713974
references: Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17089-94
references: 16287972
references: Sci Signal. 2009 Jun 16;2(75):ra28
references: 19531803
references: J Leukoc Biol. 2009 Oct;86(4):863-75
references: 19656901
references: EMBO J. 2000 Aug 15;19(16):4292-7
references: 10944112
references: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13681-6
references: 11717429
references: Nat Immunol. 2003 Apr;4(4):313-9
references: 12660731
references: Vet Immunol Immunopathol. 2003 Jun 20;93(3-4):177-84
references: 12814703
references: Philos Trans R Soc Lond B Biol Sci. 1996 Feb 29;351(1336):167-71
references: 8650263
references: Dev Comp Immunol. 2008;32(2):147-55
references: 17614130
references: Am J Respir Cell Mol Biol. 2008 Jan;38(1):26-31
references: 17690330
references: Infect Immun. 2007 Oct;75(10):5027-34
references: 17664270
references: J Immunol. 2003 Dec 15;171(12):6680-9
references: 14662871
references: J Leukoc Biol. 2007 Sep;82(3):497-508
references: 17565046
references: Cell Mol Immunol. 2007 Feb;4(1):31-41
references: 17349209
references: Immunology. 2005 Apr;114(4):507-21
references: 15804288
references: Dev Comp Immunol. 2009 May;33(5):660-7
references: 19100284
references: Innate Immun. 2008 Aug;14(4):213-22
references: 18669607
references: J Immunol. 2004 Mar 15;172(6):3814-21
references: 15004187
references: Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2764-9
references: 19188597
references: Int Immunol. 2008 May;20(5):709-18
references: 18397908
references: J Immunol. 2000 Dec 15;165(12):6682-6
references: 11120784
references: Vet Immunol Immunopathol. 2002 Sep 25;88(3-4):149-61
references: 12127413
references: Sci STKE. 2001 Jul 03;2001(89):re2
references: 11752661
references: BMC Genomics. 2008 Feb 01;9:62
references: 18241342
references: Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9577-82
references: 15976025
references: Vet Immunol Immunopathol. 2006 Jan 15;109(1-2):127-37
references: 16214221
references: FEBS Lett. 1995 May 8;364(2):229-33
references: 7750577
references: J Dermatol Sci. 2006 Apr;42(1):1-11
references: 16352421
references: Trends Immunol. 2003 Jul;24(7):358-63
references: 12860525
references: Biochem Pharmacol. 2005 Oct 15;70(8):1211-21
references: 16139249
references: J Immunol. 2000 Nov 15;165(10):5767-72
references: 11067935
references: Cell Signal. 2003 Oct;15(10):911-7
references: 12873704
references: Nat Rev Immunol. 2009 Oct;9(10):692-703
references: 19859064
references: Immunol Cell Biol. 2007 Aug-Sep;85(6):425-34
references: 17621314
references: Trends Immunol. 2009 Oct;30(10):475-87
references: 19781994
references: J Immunol. 1999 May 1;162(9):5367-73
references: 10228013
references: Biol Pharm Bull. 2007 Sep;30(9):1617-23
references: 17827709
references: J Immunol. 2001 Apr 15;166(8):5161-7
references: 11290799
references: Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17077-82
references: 16287979
references: J Immunol. 2000 Jun 1;164(11):5564-74
references: 10820230
references: Nat Immunol. 2005 Aug;6(8):751-2
references: 16034428
references: J Immunol. 2011 Feb 15;186(4):1989-96
references: 21217011
references: Microbiol Mol Biol Rev. 2011 Mar;75(1):50-83
references: 21372320
references: J Interferon Cytokine Res. 2007 Feb;27(2):97-101
references: 17316136
references: Respir Res. 2010 Jan 05;11:2
references: 20051129
references: Cell Signal. 2002 Jan;14(1):1-9
references: 11747983
references: J Endotoxin Res. 2007;13(5):281-96
references: 17986487
references: Annu Rev Biochem. 2007;76:447-80
references: 17328678
references: Dev Comp Immunol. 2003 Jun-Jul;27(6-7):621-7
references: 12697318
references: Nat Rev Immunol. 2005 Jun;5(6):446-58
references: 15928677
references: J Immunol. 2008 Feb 15;180(4):2054-61
references: 18250410
references: Dev Comp Immunol. 2005;29(9):791-807
references: 15936435
references: Infect Immun. 2001 May;69(5):2788-96
references: 11292690
references: Mol Immunol. 2009 Sep;46(15):3163-70
references: 19573927
references: Mol Immunol. 2007 May;44(12):3234-42
references: 17339052
references: Dev Comp Immunol. 2005;29(3):255-64
references: 15572073
references: J Immunol. 2000 Dec 15;165(12):7096-101
references: 11120839
references: Infect Immun. 2006 Mar;74(3):1692-8
references: 16495540
references: Mol Immunol. 2008 Mar;45(5):1298-307
references: 17964652
references: Immunobiology. 2006;211(6-8):511-24
references: 16920490
references: Nat Immunol. 2005 Aug;6(8):777-84
references: 16007092
references: J Immunol. 2009 Dec 15;183(12):8110-8
references: 19923461
references: Immunology. 2005 Oct;116(2):203-12
references: 16162269
references: J Immunol. 2009 May 1;182(9):5225-31
references: 19380768
references: Immunogenetics. 2009 Jan;61(1):71-7
references: 19002681