title: Proinflammatory S100A12 can activate human monocytes via Toll-like receptor 4.
abstract: BACKGROUND
  S100A12 is overexpressed during inflammation and is a marker of inflammatory disease. Furthermore, it has been ascribed to the group of damage-associated molecular pattern molecules that promote inflammation. However, the exact role of human S100A12 during early steps of immune activation and sepsis is only partially described thus far.
  
  
  OBJECTIVE
  We analyzed the activation of human monocytes by granulocyte-derived S100A12 as a key function of early inflammatory processes and the development of sepsis.
  
  
  METHODS
  Circulating S100A12 was determined in patients with sepsis and in healthy subjects with experimental endotoxemia. The release of human S100A12 from granulocytes as well as the promotion of inflammation by activation of human monocytes after specific receptor interaction was investigated by a series of in vitro experiments.
  
  
  RESULTS
  S100A12 rises during sepsis, and its expression and release from granulocytes is rapidly induced in vitro and in vivo by inflammatory challenge. A global gene expression analysis of S100A12-activated monocytes revealed that human S100A12 induces inflammatory gene expression. These effects are triggered by an interaction of S100A12 with Toll-like receptor 4 (TLR4). Blocking S100A12 binding to TLR4 on monocytes or TLR4 expressing cell lines (HEK-TCM) abrogates the respective inflammatory signal. On the contrary, blocking S100A12 binding to its second proposed receptor (receptor for advanced glycation end products [RAGE]) has no significant effect on inflammatory signaling in monocytes and RAGE-expressing HEK293 cells.
  
  
  CONCLUSIONS
  Human S100A12 is an endogenous TLR4 ligand that induces monocyte activation, thereby acting as an amplifier of innate immunity during early inflammation and the development of sepsis.
authors.affiliation: Department of Pediatric Rheumatology and Immunology, University Children's Hospital Muenster, Muenster, Germany. dfoell@uni-muenster.de
authors.forename: Dirk
authors.initials: D
authors.lastname: Foell
authors.forename: Helmut
authors.initials: H
authors.lastname: Wittkowski
authors.forename: Christoph
authors.initials: C
authors.lastname: Kessel
authors.forename: Aloys
authors.initials: A
authors.lastname: Lüken
authors.forename: Toni
authors.initials: T
authors.lastname: Weinhage
authors.forename: Georg
authors.initials: G
authors.lastname: Varga
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.forename: Timo
authors.initials: T
authors.lastname: Wirth
authors.forename: Dorothee
authors.initials: D
authors.lastname: Viemann
authors.forename: Per
authors.initials: P
authors.lastname: Björk
authors.forename: Marieke A D
authors.initials: MA
authors.lastname: van Zoelen
authors.forename: Faekah
authors.initials: F
authors.lastname: Gohar
authors.forename: Geetha
authors.initials: G
authors.lastname: Srikrishna
authors.forename: Matthias
authors.initials: M
authors.lastname: Kraft
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology*; D009418:S100 Proteins / Q000097:blood / Q000502:physiology*; D000067616:S100A12 Protein; D018805:Sepsis / Q000097:blood / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000097:blood / Q000502:physiology*; D055815:Young Adult
chemical_list: D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D051197:Toll-Like Receptor 4