title: Inhibition of interleukin-6-transsignaling via gp130-Fc in hemorrhagic shock and sepsis.
abstract: BACKGROUND
  Immune function after hemorrhagic shock and subsequent sepsis is characterized by an early proinflammatory burst of IL-6, and high IL-6 levels have been linked to high mortality after trauma and in sepsis. Trans-signaling is defined as the activation of cells that do not express the membrane bound IL-6 receptor by the complex of IL-6 and the soluble IL-6 receptor (sIL-6R). Gp130-Fc is able to bind the IL-6/sIL-6R complex, and beneficial effects of IL-6 blockade in chronic inflammatory diseases have been shown. The first aim of this study was to investigate the potential effect of a gp130 blockade via the gp130-Fc antibody causing impairment of IL-6 signaling. The second aim was to find out what role the IL-6/sIL-6R complex can play in the context of hemorrhagic shock and subsequent sepsis as an acute inflammatory disease.
  
  
  METHODS
  Male CBA/J mice were subjected to hemorrhagic shock (35+/-5 mmHg for 90min and fluid resuscitation) or sham operation. At resuscitation each animal received either 0.5mg gp130-Fc or placebo (PL) i.p. At 48 h after resuscitation, both splenocytes and peritoneal macrophages (pMphi) were harvested or polymicrobial sepsis was induced by cecal ligation and puncture. Survival over 10 d was determined. Release of IL-6, TNF-alpha, and IL-10 of pMphi and release of IL-2, IL-10, and IFN-gamma of splenocytes was assessed by ELISA. Proliferation of splenocytes and their morphologic damage were determined.
  
  
  RESULTS
  Binding of the IL-6/sIL-6R complex by gp130-Fc led to significant lower IL-6 levels compared with placebo treated animals. Placebo treated males showed depressed proinflammatory immune response (IL-2, IL-6) after hemorrhagic shock. While splenocyte proliferation was significantly reduced directly after hemorrhagic shock and restored after 48 h by gp130-Fc, pMphi cytokine release was not influenced. Finally, survival appeared to be unaffected.
  
  
  CONCLUSIONS
  Transsignaling does not seem to play a pivotal role in the development of the immune dysfunction and mortality in our model of hemorrhage and subsequent sepsis.
authors: Department of General Surgery, University of Muenster, Muenster, Germany. soerentorge.mees@ukmuenster.de
authors: Soeren Torge
authors: ST
authors: Mees
authors: Sietje
authors: S
authors: Toellner
authors: Kerstin
authors: K
authors: Marx
authors: Fred
authors: F
authors: Faendrich
authors: Karl Josef
authors: KJ
authors: Kallen
authors: Joerg
authors: J
authors: Schroeder
authors: Joerg
authors: J
authors: Haier
authors: Volker
authors: V
authors: Kahlke
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D007082:Ileum / Q000473:pathology; D007107:Immune System / Q000187:drug effects / Q000502:physiology; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D015846:Monokines / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018805:Sepsis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012771:Shock, Hemorrhagic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000093242:Interleukin-6 Inhibitors
chemical_list: D000906:Antibodies; D050822:Cytokine Receptor gp130; D015850:Interleukin-6; D015846:Monokines; D019947:Receptors, Interleukin-6; D000093242:Interleukin-6 Inhibitors