title: A central role for monocytes in Toll-like receptor-mediated activation of the vasculature.
abstract: There is increasing evidence that activation of inflammatory responses in a variety of tissues is mediated co-operatively by the actions of more than one cell type. In particular, the monocyte has been implicated as a potentially important cell in the initiation of inflammatory responses to Toll-like receptor (TLR)-activating signals. To determine the potential for monocyte-regulated activation of tissue cells to underpin inflammatory responses in the vasculature, we established cocultures of primary human endothelial cells and monocytes and dissected the inflammatory responses of these systems following activation with TLR agonists. We observed that effective activation of inflammatory responses required bidirectional signalling between the monocyte and the tissue cell. Activation of cocultures was dependent on interleukin-1 (IL-1). Although monocyte-mediated IL-1beta production was crucial to the activation of cocultures, TLR specificity to these responses was also provided by the endothelial cells, which served to regulate the signalling of the monocytes. TLR4-induced IL-1beta production by monocytes was increased by TLR4-dependent endothelial activation in coculture, and was associated with increased monocyte CD14 expression. Activation of this inflammatory network also supported the potential for downstream monocyte-dependent T helper type 17 activation. These data define co-operative networks regulating inflammatory responses to TLR agonists, identify points amenable to targeting for the amelioration of vascular inflammation, and offer the potential to modify atherosclerotic plaque instability after a severe infection.
authors.affiliation: Cardiovascular Research Unit, School of Medicine and Biomedical Sciences, The University of Sheffield, Sheffield, UK.
authors.forename: Jon R
authors.initials: JR
authors.lastname: Ward
authors.forename: Sheila E
authors.initials: SE
authors.lastname: Francis
authors.forename: Luke
authors.initials: L
authors.lastname: Marsden
authors.forename: Tesha
authors.initials: T
authors.lastname: Suddason
authors.forename: Graham M
authors.initials: GM
authors.lastname: Lord
authors.forename: Steven K
authors.initials: SK
authors.lastname: Dower
authors.forename: David C
authors.initials: DC
authors.lastname: Crossman
authors.forename: Ian
authors.initials: I
authors.lastname: Sabroe
mesh_terms: D002450:Cell Communication / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D042783:Endothelial Cells / Q000276:immunology; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D009000:Monocytes / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000819:agonists; D051193:Toll-Like Receptors / Q000276:immunology*
chemical_list: D016207:Cytokines; D007375:Interleukin-1; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors
references.citation: Blood. 2007 Feb 15;109(4):1574-83
references.pmid: 17038528
references.citation: Circulation. 2008 May 20;117(20):2670-83
references.pmid: 18474815
references.citation: Annu Rev Pathol. 2008;3:99-126
references.pmid: 18039143
references.citation: Thromb Haemost. 2005 Oct;94(4):831-8
references.pmid: 16270639
references.citation: J Allergy Clin Immunol. 2007 Aug;120(2):247-54
references.pmid: 17666214
references.citation: Circ Res. 2001 Aug 3;89(3):244-50
references.pmid: 11485974
references.citation: Clin Exp Immunol. 2007 Feb;147(2):199-207
references.pmid: 17223959
references.citation: Cardiovasc Res. 2005 Dec 1;68(3):493-501
references.pmid: 16099441
references.citation: J Endotoxin Res. 2006;12(3):133-50
references.pmid: 16719986
references.citation: N Engl J Med. 2002 Jul 18;347(3):185-92
references.pmid: 12124407
references.citation: Curr Opin Immunol. 2007 Jun;19(3):281-6
references.pmid: 17433650
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1966-71
references.pmid: 12569171
references.citation: Circulation. 2002 Mar 12;105(10):1158-61
references.pmid: 11889007
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17034-9
references.pmid: 17942669
references.citation: Curr Opin Investig Drugs. 2005 May;6(5):496-502
references.pmid: 15912963
references.citation: Clin Immunol. 2008 Apr;127(1):89-97
references.pmid: 18294918
references.citation: J Immunol. 2001 Jan 1;166(1):249-55
references.pmid: 11123299
references.citation: J Biol Chem. 2000 Apr 14;275(15):11058-63
references.pmid: 10753909
references.citation: J Immunol. 2002 May 1;168(9):4701-10
references.pmid: 11971020
references.citation: FASEB J. 2006 Oct;20(12):2153-5
references.pmid: 16935934
references.citation: J Exp Med. 1993 Dec 1;178(6):2193-200
references.pmid: 7504060
references.citation: J Biol Chem. 1997 May 2;272(18):11778-85
references.pmid: 9115233
references.citation: J Endotoxin Res. 2001;7(4):322-6
references.pmid: 11717590
references.citation: N Engl J Med. 2004 Dec 16;351(25):2611-8
references.pmid: 15602021
references.citation: J Immunol. 2008 Oct 15;181(8):5606-17
references.pmid: 18832719
references.citation: J Leukoc Biol. 2004 Sep;76(3):514-9
references.pmid: 15178705
references.citation: Br J Pharmacol. 2007 May;151(1):115-27
references.pmid: 17351655
references.citation: Am J Respir Crit Care Med. 2005 Apr 15;171(8):814-22
references.pmid: 15657467
references.citation: Annu Rev Immunol. 2007;25:821-52
references.pmid: 17201677
references.citation: J Am Coll Cardiol. 1999 Dec;34(7):1975-81
references.pmid: 10588212
references.citation: Atherosclerosis. 2007 Feb;190(2):443-51
references.pmid: 16569408
references.citation: Am Heart J. 2005 Sep;150(3):488-99
references.pmid: 16169330
references.citation: Nat Med. 2007 Jul;13(7):851-6
references.pmid: 17572686
references.citation: J Immunol. 1991 Mar 1;146(5):1437-45
references.pmid: 1993838
references.citation: J Immunol. 2003 Aug 15;171(4):1630-5
references.pmid: 12902458
references.citation: N Engl J Med. 2005 Apr 21;352(16):1685-95
references.pmid: 15843671
references.citation: J Clin Invest. 2003 Apr;111(7):1011-20
references.pmid: 12671050
references.citation: Am J Pathol. 2006 Apr;168(4):1396-403
references.pmid: 16565512
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10679-84
references.pmid: 15249654
references.citation: Immunity. 2001 Nov;15(5):825-35
references.pmid: 11728343