title: CD166/ALCAM mediates proinflammatory effects of S100B in delayed type hypersensitivity.
abstract: Promiscuity of pattern recognition receptors, such as receptor for advanced glycation end products (RAGE), allows for a complex regulatory network controlling inflammation. Scavenging of RAGE ligands by soluble RAGE treatment is effective in reducing delayed-type hypersensitivity (DTH), even in RAGE(-/-) mice by 50% (p < 0.001). This has led to the hypothesis that molecules scavenged by soluble RAGE bind to receptors other than RAGE. This study identifies CD166/ALCAM (ALCAM) as a close structural and functional homolog of RAGE, and it shows that binding of S100B to CD166/ALCAM induces dose- and time-dependent expression of members of the NF-κB family in wild type (WT) and RAGE(-/-) mouse endothelial cells. Blocking CD166/ALCAM expression using small interfering RNA completely inhibited S100B-induced NF-κB activation in RAGE(-/-), but not in WT cells. The in vivo significance of these observations was demonstrated by attenuation of DTH in WT and RAGE(-/-) animals pretreated with CD166/ALCAM small interfering RNA by 50% and 40%, respectively (p < 0.001). Experiments in ALCAM(-/-) animals displayed an only slight reduction of 16% in DTH, explained by compensatory reciprocal upregulation of RAGE in animals devoid of CD166/ALCAM, and vice versa. Consistently, ALCAM(-/-) mice, but not WT mice treated with RAGE small interfering RNA show a 35% reduction in DTH, and ALCAM(-/-) RAGE(-/-) double-knockout mice show a 27% reduction in DTH reaction. Thus, S100B is a proinflammatory cytokine bridging RAGE and CD166/ALCAM downstream effector mechanisms, both being compensatory upregulated after genetic deletion of its counterpart.
authors.affiliation: Department of Medicine I and Clinical Chemistry, University of Heidelberg, D-69120 Heidelberg, Germany. ruediger.vonbauer@med.uni-heidelberg.de
authors.forename: Rüdiger
authors.initials: R
authors.lastname: von Bauer
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Oikonomou
authors.forename: Alba
authors.initials: A
authors.lastname: Sulaj
authors.forename: Sawsan
authors.initials: S
authors.lastname: Mohammed
authors.forename: Agnes
authors.initials: A
authors.lastname: Hotz-Wagenblatt
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.forename: Christine
authors.initials: C
authors.lastname: Falk
authors.forename: Dorit
authors.initials: D
authors.lastname: Luethje
authors.forename: Axel
authors.initials: A
authors.lastname: Erhardt
authors.forename: David M
authors.initials: DM
authors.lastname: Stern
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
mesh_terms: D000071916:AC133 Antigen; D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000502:physiology*; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D010455:Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D013329:Structure-Activity Relationship; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000071916:AC133 Antigen; D020410:Activated-Leukocyte Cell Adhesion Molecule; D015703:Antigens, CD; D006023:Glycoproteins; D018836:Inflammation Mediators; D009414:Nerve Growth Factors; D010455:Peptides; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; C579159:S100b protein, mouse