title: Soluble CEACAM8 interacts with CEACAM1 inhibiting TLR2-triggered immune responses.
abstract: Lower respiratory tract bacterial infections are characterized by neutrophilic inflammation in the airways. The carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 8 is expressed in and released by human granulocytes. Our study demonstrates that human granulocytes release CEACAM8 in response to bacterial DNA in a TLR9-dependent manner. Individuals with a high percentage of bronchial lavage fluid (BALF) granulocytes were more likely to have detectable levels of released CEACAM8 in the BALF than those with a normal granulocyte count. Soluble, recombinant CEACAM8-Fc binds to CEACAM1 expressed on human airway epithelium. Application of CEACAM8-Fc to CEACAM1-positive human pulmonary epithelial cells resulted in reduced TLR2-dependent inflammatory responses. These inhibitory effects were accompanied by tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM) of CEACAM1 and by recruitment of the phosphatase SHP-1, which could negatively regulate Toll-like receptor 2-dependent activation of the phosphatidylinositol 3-OH kinase-Akt kinase pathway. Our results suggest a new mechanism by which granulocytes reduce pro-inflammatory immune responses in human airways via secretion of CEACAM8 in neutrophil-driven bacterial infections.
authors.affiliation: Institute of Anatomy, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Bernhard B
authors.initials: BB
authors.lastname: Singer
authors.affiliation: Institute of Microbiology and Hygiene, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Opp
authors.affiliation: Institute of Microbiology and Hygiene, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Annina
authors.initials: A
authors.lastname: Heinrich
authors.affiliation: Institute of Microbiology and Hygiene, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Schreiber
authors.affiliation: Institute of Microbiology and Hygiene, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Binding-Liermann
authors.affiliation: Institute of Microbiology and Hygiene, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Luis Carlos
authors.initials: LC
authors.lastname: Berrocal-Almanza
authors.affiliation: ZIK Septomics, University Hospital Jena, Jena, Germany.
authors.forename: Kerstin A
authors.initials: KA
authors.lastname: Heyl
authors.affiliation: ZIK Septomics, University Hospital Jena, Jena, Germany.
authors.forename: Mario M
authors.initials: MM
authors.lastname: Müller
authors.affiliation: Labor Berlin - Charité Vivantes Services GmbH, Berlin, Germany; Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry of the Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Weimann
authors.affiliation: Institute of Hygiene and Environmental Medicine, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Zweigner
authors.affiliation: ZIK Septomics, University Hospital Jena, Jena, Germany.
authors.forename: Hortense
authors.initials: H
authors.lastname: Slevogt
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism*; D001980:Bronchi / Q000166:cytology / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000378:metabolism*; D002452:Cell Count; D002460:Cell Line; D015638:Cytochalasin D / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000737:chemistry / Q000378:metabolism; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D011485:Protein Binding; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; C504120:CEACAM8 protein, human; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051217:Toll-Like Receptor 9; D015638:Cytochalasin D
references.citation: J Immunol. 2007 Dec 15;179(12):8454-62
references.pmid: 18056392
references.citation: J Leukoc Biol. 1992 Nov;52(5):551-7
references.pmid: 1431566
references.citation: Cell Microbiol. 2011 Mar;13(3):432-49
references.pmid: 21044239
references.citation: BMC Evol Biol. 2007 Oct 18;7:196
references.pmid: 17945019
references.citation: J Leukoc Biol. 2012 May;91(5):791-802
references.pmid: 22319104
references.citation: J Leukoc Biol. 2003 Jul;74(1):126-34
references.pmid: 12832451
references.citation: Infect Immun. 2009 Feb;77(2):568-75
references.pmid: 19015252
references.citation: Br J Haematol. 2004 Jun;125(5):666-73
references.pmid: 15147383
references.citation: J Immunol. 2009 Apr 1;182(7):4386-94
references.pmid: 19299739
references.citation: PLoS One. 2010 Jan 18;5(1):e8747
references.pmid: 20090913
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 May;290(5):L818-26
references.pmid: 16399788
references.citation: J Leukoc Biol. 2009 Aug;86(2):205-18
references.pmid: 19454653
references.citation: Immunol Invest. 1995 Aug;24(5):829-43
references.pmid: 8543346
references.citation: Nat Rev Immunol. 2006 Jun;6(6):433-46
references.pmid: 16724098
references.citation: Semin Respir Crit Care Med. 2007 Oct;28(5):546-60
references.pmid: 17975782
references.citation: Immunology. 2010 Jan;129(1):55-61
references.pmid: 20050330
references.citation: Am J Respir Cell Mol Biol. 2011 Aug;45(2):189-201
references.pmid: 21330463
references.citation: Eur J Immunol. 1998 Nov;28(11):3664-74
references.pmid: 9842909
references.citation: Immunity. 2010 Oct 29;33(4):620-31
references.pmid: 21029969
references.citation: J Clin Invest. 1997 Jul 1;100(1):68-73
references.pmid: 9202058
references.citation: PLoS Pathog. 2012;8(4):e1002597
references.pmid: 22496641
references.citation: Nat Immunol. 2008 Nov;9(11):1270-8
references.pmid: 18836450
references.citation: J Immunol. 2004 Apr 15;172(8):4956-63
references.pmid: 15067076
references.citation: Am J Physiol Cell Physiol. 2007 May;292(5):C1690-700
references.pmid: 17202227
references.citation: Am J Respir Crit Care Med. 2012 May 1;185(9):1004-14
references.pmid: 22550210
references.citation: Nat Rev Immunol. 2011 Jul 25;11(8):519-31
references.pmid: 21785456
references.citation: J Immunol. 2008 Dec 1;181(11):8053-67
references.pmid: 19017998
references.citation: Clin Exp Immunol. 2011 Sep;165(3):292-300
references.pmid: 21671907
references.citation: J Immunol. 2002 May 15;168(10):5139-46
references.pmid: 11994468
references.citation: Cell Microbiol. 2007 Mar;9(3):694-707
references.pmid: 17054439