title: Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model.
abstract: OBJECTIVE
  The pleiotropic cytokine interleukin (IL)-6 seems to play a pivotal role in sepsis, but contradictory findings in animal models impede a rationale for therapies directed against IL-6. IL-6 signals by two mechanisms via the ubiquitous transmembrane glycoprotein 130 (gp130): "classic" signaling using membrane-bound IL-6 receptor (IL-6R) and trans-signaling using soluble IL-6R (sIL-6R). Trans-signaling is selectively inhibited by soluble gp130 (sgp130). The aim of this study was to systematically compare complete blockade of IL-6 signaling (using a neutralizing anti-IL-6 antibody) and selective blockade of IL-6 trans-signaling (using a fusion protein of sgp130 and the crystallizable fragment of immunoglobulin G1, sgp130Fc) in a standardized cecal ligation and puncture (CLP) sepsis model.
  
  
  METHODS
  Animal study.
  
  
  METHODS
  Animal laboratory.
  
  
  METHODS
  C57BL/6J mice.
  
  
  METHODS
  We performed a 96-hr dose-response study and a 24-hr study to investigate short-term mechanisms. In the 96-hr study, CLP was performed in 120 randomized mice (20 mice received vehicle, 10 mice per dose group). Mice were treated with equimolar doses of sgp130Fc (0.01/0.1/1/10 mg/kg) or anti-IL-6 (0.008/0.08/0.8/8 mg/kg) 24 hrs before CLP. Two additional groups received 0.5 mg/kg sgp130Fc 24 hrs before or 1 mg/kg sgp130Fc 24 hrs after CLP. Survival and activity scores were obtained daily until 96 hrs after CLP. In the 24-hr study, mice were randomized into four groups with 10 animals each (sham/vehicle, CLP/vehicle, CLP/anti-IL-6 [0.8 mg/kg], and CLP/sgp130Fc [1 mg/kg]) and killed after 24 hrs.
  
  
  RESULTS
  In contrast to anti-IL-6, pretreatment with sgp130Fc significantly and dose-dependently increased survival from 45% to 100%. In addition, 1 mg/kg sgp130Fc administered 24 hrs after CLP increased survival from 45% to 80%. Mechanistically, sgp130Fc efficacy was reflected by complete prevention of epithelial cell apoptosis in the jejunum after CLP, which was not achieved with anti-IL-6.
  
  
  CONCLUSIONS
  Selective inhibition of IL-6 trans-signaling by sgp130Fc has considerable potential for the treatment of sepsis and related disorders.
authors.affiliation: Trauma Department, Hannover Medical School, Hannover, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Barkhausen
authors.forename: Thomas
authors.initials: T
authors.lastname: Tschernig
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: Martijn
authors.initials: M
authors.lastname: van Griensven
authors.forename: Ralf-Peter
authors.initials: RP
authors.lastname: Vonberg
authors.forename: Martina
authors.initials: M
authors.lastname: Dorsch
authors.forename: Annika
authors.initials: A
authors.lastname: Mueller-Heine
authors.forename: Athena
authors.initials: A
authors.lastname: Chalaris
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Dirk
authors.initials: D
authors.lastname: Seegert
authors.forename: Christian
authors.initials: C
authors.lastname: Krettek
authors.forename: Georg H
authors.initials: GH
authors.lastname: Waetzig
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015850:Interleukin-6 / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D018805:Sepsis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors
chemical_list: D057134:Antibodies, Neutralizing; D015850:Interleukin-6; D011993:Recombinant Fusion Proteins; D000093242:Interleukin-6 Inhibitors; C519852:olamkicept