title: Inhibition of CCL20 increases mortality in models of mouse sepsis with intestinal apoptosis.
abstract: BACKGROUND
  CC chemokine ligand 20 (CCL20) and CC chemokine receptor 6 are believed to stimulate the recruitment of neutrophils and activation of macrophages against bacterial pathogens through the activation of T helper cells. We analyzed the role of CCL20 in the acute phase of sepsis.
  
  
  METHODS
  The effect of a neutralizing, anti-mouse CCL20 monoclonal antibody (mAb) was examined in 2 murine models of sepsis: Cecal ligation and puncture (CLP) and Escherichia coli peritonitis. Immune cell migration, bacterial clearance, and expression of 17 cytokines and 5 chemokines were quantified in E coli-induced peritonitis. Expression of CCL20 in various tissues was determined, and apoptotic cells in jejunum were measured.
  
  
  RESULTS
  Anti-CCL20 mAb increased mortality in CLP and E coli peritonitis (P = .029 and .024, respectively by Kaplan-Meier method and log-rank test). The 48-hour survival rate in anti-CCL20 mAb- and control immunoglobulin (Ig)G-treated mice was 37% (11/30) vs 62% (18/29) in CLP and 28% (11/40) vs 48% (19/40) in bacterial peritonitis. Neutralization of CCL20 showed no effect on leukocyte infiltration into the peritoneal cavity or bacterial clearance at 24 hours. CCL20 was induced strongly and predominantly in jejunum after bacterial infection, and neutralizing CCL20 increased apoptosis of epithelial cells in jejunum crypt. Inhibition of CCL20 increased serum tumor necrosis factor (TNF)-α (3.3-fold greater than control mice) and decreased serum interleukin (IL)-1α and IL-6.
  
  
  CONCLUSIONS
  Neutralization of CCL20 before induction of sepsis increased mortality during sepsis accompanied with increasing epithelial apoptosis in the jejunum and augmenting serum TNF-α.
authors.affiliation: KAN Research Institute Inc, Kobe, Hyogo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kitagawa
authors.forename: Shojiro
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Arita
authors.forename: Miyuki
authors.initials: M
authors.lastname: Nishimura
authors.forename: Keiko
authors.initials: K
authors.lastname: Mizuno
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ogasawara
authors.forename: Tetsu
authors.initials: T
authors.lastname: Kawano
authors.forename: Toshiya
authors.initials: T
authors.lastname: Ochiai
authors.forename: Eigo
authors.initials: E
authors.lastname: Otsuji
authors.forename: Toshio
authors.initials: T
authors.lastname: Imai
mesh_terms: D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D054418:Chemokine CCL20 / Q000037:antagonists & inhibitors / Q000502:physiology*; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D007583:Jejunum / Q000473:pathology*; D007962:Leukocytes / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010529:Peritoneal Cavity / Q000166:cytology; D010538:Peritonitis / Q000382:microbiology; D018805:Sepsis / Q000401:mortality*; D058504:Th17 Cells / Q000502:physiology
chemical_list: C493447:CCL20 protein, mouse; D054418:Chemokine CCL20; D018925:Chemokines; D016207:Cytokines