title: Extracellular ATP and Toll-like receptor 2 agonists trigger in human monocytes an activation program that favors T helper 17.
abstract: Strategically-paired Toll-like receptor (TLR) ligands induce a unique dendritic cell (DC) phenotype that polarizes Th1 responses. We therefore investigated pairing single TLR ligands with a non TLR-mediated danger signal to cooperatively induce distinct DC properties from cultured human monocytes. Adenosine triphosphate (ATP) and the TLR2 ligand lipoteichoic acid (LTA) selectively and synergistically induced expression of IL-23 and IL-1β from cultured monocytes as determined by ELISA assays. Flow cytometric analysis revealed that a sizable sub-population of treated cells acquired DC-like properties including activated surface phenotype with trans-well assays showing enhanced migration towards CCR7 ligands. Such activated cells also preferentially deviated, in an IL-23 and IL-1-dependent manner, CD4(pos) T lymphocyte responses toward the IL-22(hi), IL-17(hi)/IFN-γ(lo) Th17 phenotype in standard in vitro allogeneic sensitization assays. Although pharmacological activation of either ionotropic or cAMP-dependent pathways acted in synergy with LTA to enhance IL-23, only inhibition of the cAMP-dependent pathway antagonized ATP-enhanced cytokine production. ATP plus atypical lipopolysaccharide from P. gingivalis (signaling through TLR2) was slightly superior to E. coli-derived LPS (TLR4 ligand) for inducing the high IL-23-secreting DC-like phenotype, but greatly inferior for inducing IL-12 p70 production when paired with IFN-γ, a distinction reflected in activated DCs' ability to deviate lymphocytes toward Th1. Collectively, our data suggest TLR2 ligands encountered by innate immune cells in an environment with physiologically-relevant levels of extracellular ATP can induce a distinct activation state favoring IL-23- and IL-1β-dependent Th17 type response.
authors: Department of Biological Sciences, Biomedical Sciences Program, Kent State University, Kent, Ohio, USA.
authors: Christopher
authors: C
authors: Paustian
authors: Patricia
authors: P
authors: Taylor
authors: Terrence
authors: T
authors: Johnson
authors: Min
authors: M
authors: Xu
authors: Nancy
authors: N
authors: Ramirez
authors: Kenneth S
authors: KS
authors: Rosenthal
authors: Suyu
authors: S
authors: Shu
authors: Peter A
authors: PA
authors: Cohen
authors: Brian J
authors: BJ
authors: Czerniecki
authors: Gary K
authors: GK
authors: Koski
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D018836:Inflammation Mediators; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D010641:Phenotype; D021122:Protein Subunits; D015398:Signal Transduction; D013682:Teichoic Acids / Q000494:pharmacology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D021122:Protein Subunits; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C009900:lipoteichoic acid; D000255:Adenosine Triphosphate; D000262:Adenylyl Cyclases
references: Surgery. 2006 Aug;140(2):170-8
references: 16904966
references: J Exp Med. 2009 Jul 6;206(7):1457-64
references: 19564351
references: Infect Immun. 2010 Jan;78(1):381-6
references: 19822653
references: Nat Immunol. 2008 Jun;9(6):650-7
references: 18454150
references: Curr Opin Investig Drugs. 2009 Jun;10(6):543-9
references: 19513943
references: Rheumatology (Oxford). 2007 Aug;46(8):1266-73
references: 17569750
references: J Biol Chem. 1996 Nov 22;271(47):29830-8
references: 8939922
references: Nature. 2006 May 11;441(7090):235-8
references: 16648838
references: Science. 1997 Jan 10;275(5297):206-9
references: 8999548
references: Eur J Immunol. 2001 Dec;31(12):3773-81
references: 11745398
references: Nature. 2006 Jul 27;442(7101):461-5
references: 16688182
references: Nature. 2012 Jan 18;481(7381):278-86
references: 22258606
references: J Clin Microbiol. 2010 May;48(5):1949-51
references: 20305009
references: Self Nonself. 2010 Jul;1(3):250-254
references: 21487481
references: J Immunol. 2008 Jun 1;180(11):7423-30
references: 18490742
references: Asian Pac J Cancer Prev. 2006 Jan-Mar;7(1):163
references: 16685780
references: Nat Immunol. 2005 Nov;6(11):1133-41
references: 16200068
references: Nat Immunol. 2007 Sep;8(9):950-7
references: 17676044
references: PLoS One. 2008 Jul 09;3(7):e2599
references: 18612415
references: Cancer Cell. 2009 Feb 3;15(2):114-23
references: 19185846
references: Cancer Res. 2007 Feb 15;67(4):1842-52
references: 17293384
references: Annu Rev Immunol. 1994;12:991-1045
references: 8011301
references: J Biol Chem. 2009 Sep 4;284(36):24006-16
references: 19592489
references: Blood. 2009 Jul 9;114(2):357-9
references: 19289853
references: Int Immunol. 1998 Nov;10(11):1593-8
references: 9846688
references: J Exp Med. 2005 Jan 17;201(2):233-40
references: 15657292
references: J Immunol. 1997 Oct 15;159(8):3823-37
references: 9378970
references: Immunity. 2006 Mar;24(3):317-27
references: 16546100
references: Nat Immunol. 2005 Aug;6(8):769-76
references: 15995707
references: Lancet. 1994 Jan 29;343(8892):258-60
references: 7905095
references: Immunity. 2007 Oct;27(4):549-59
references: 17967410
references: FEMS Immunol Med Microbiol. 2007 Dec;51(3):577-86
references: 17919297
references: Nature. 2009 Jan 1;457(7225):102-6
references: 19122641
references: J Exp Med. 1990 Sep 1;172(3):921-9
references: 2117636
references: Biochem Biophys Res Commun. 2008 Sep 26;374(3):533-7
references: 18655770
references: Clin Exp Allergy. 2006 Nov;36(11):1357-66
references: 17083345
references: FEMS Immunol Med Microbiol. 2007 Oct;51(1):140-8
references: 17645528
references: Immunol Rev. 2000 Feb;173:89-97
references: 10719670
references: Nat Immunol. 2008 Jun;9(6):641-9
references: 18454151
references: Blood. 2009 Aug 6;114(6):1141-9
references: 19470694
references: Curr Opin Immunol. 2001 Feb;13(1):114-9
references: 11154927
references: J Immunol. 2008 Jul 1;181(1):721-35
references: 18566439
references: EMBO J. 2006 Nov 1;25(21):5071-82
references: 17036048
references: J Exp Med. 1993 Apr 1;177(4):1199-204
references: 8096238
references: J Immunol. 2000 Jan 15;164(2):558-61
references: 10623794
references: J Immunol. 2002 Jun 1;168(11):5771-7
references: 12023378
references: Immunity. 2004 Mar;20(3):319-25
references: 15030775
references: Nature. 2008 Oct 9;455(7214):808-12
references: 18716618
references: J Immunol. 2004 Apr 1;172(7):3989-93
references: 15034009
references: Blood. 2005 Feb 15;105(4):1582-9
references: 15486065
references: Blood. 2008 Jul 15;112(2):362-73
references: 18354038
references: J Immunol. 2009 Aug 15;183(4):2242-51
references: 19625644
references: Cancer Cell. 2005 Mar;7(3):211-7
references: 15766659
references: Immunol Rev. 2008 Dec;226:112-31
references: 19161420
references: J Immunol. 2008 Oct 1;181(7):5120-7
references: 18802116
references: Semin Immunol. 2007 Dec;19(6):377-82
references: 18054248
references: Nat Immunol. 2006 Jun;7(6):569-75
references: 16648853
references: Mol Cell. 2002 Aug;10(2):417-26
references: 12191486
references: FEBS Lett. 1999 Sep 24;458(3):424-8
references: 10570953
references: J Immunol. 2000 Oct 1;165(7):3647-55
references: 11034368
references: Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9479-84
references: 15194822
references: Nature. 1997 Jul 24;388(6640):394-7
references: 9237759
references: Immunity. 2008 Apr;28(4):454-67
references: 18400188
references: J Exp Med. 2003 Dec 15;198(12):1875-86
references: 14676299
references: Nat Immunol. 2007 Jun;8(6):639-46
references: 17486092
references: Infect Immun. 2001 Mar;69(3):1477-82
references: 11179315
references: Blood. 2001 Feb 1;97(3):587-600
references: 11157473
references: Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6232-7
references: 19325128
references: Clin Exp Allergy. 1999 Jun;29 Suppl 2:33-6
references: 10421820
references: J Biol Chem. 2002 Jun 7;277(23):20847-53
references: 11912201
references: Science. 1999 Jul 30;285(5428):732-6
references: 10426995
references: Nat Immunol. 2005 Nov;6(11):1123-32
references: 16200070